Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors

ABSTRACT

This invention pertains to certain carbamic acid compounds which inhibit HDAC (histone deacetylase) activity of the following formula: 
                         
The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.

This application is a continuation of application Ser. No. 10/509,732,filed Sep. 30, 2004 (pending), which is the U.S. national phase ofinternational application PCT/GB03/01463 filed Apr. 3, 2003 whichdesignated the US, and which claims the benefit of U.S. ProvisionalApplication No. 60/369,337 filed Apr. 3, 2002, the entire contents ofeach of which is hereby incorporated by reference.

TECHNICAL FIELD

This invention pertains generally to the field of biologically activecompounds, and more specifically to certain carbamic acid compoundswhich inhibit HDAC (histone deacetylase) activity. The present inventionalso pertains to pharmaceutical compositions comprising such compounds,and the use of such compounds and compositions, both in vitro and invivo, to inhibit HDAC, and in the treatment of conditions mediated byHDAC, cancer, proliferative conditions, psoriasis, etc.

BACKGROUND

Throughout this specification, including any claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps, butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and any appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

DNA in eukaryotic cells is tightly complexed with proteins (histones) toform chromatin. Histones are small, positively charged proteins whichare rich in basic amino acids (positively charged at physiological pH),which contact the phosphate groups (negatively charged at physiologicalpH) of DNA. There are five main classes of histones, H1, H2A, H2B, H3,and H4. The amino acid sequences of histones H2A, H2B, H3, and H4 showremarkable conservation between species, whereas H1 varies somewhat, andin some cases is replaced by another histone, e.g., H5. Four pairs ofeach of H2A, H2B, H3, and H4 together form a disk-shaped octomericprotein core, around which DNA (about 140 base pairs) is wound to form anucleosome. Individual nucleosomes are connected by short stretches oflinker DNA associated with another histone molecule (e.g., H1, or incertain cases, H5) to form a structure resembling a beaded string, whichis itself arranged in a helical stack, known as a solenoid.

The majority of histones are synthesised during the S phase of the cellcycle, and newly synthesised histones quickly enter the nucleus tobecome associated with DNA. Within minutes of its synthesis, new DNAbecomes associated with histones in nucleosomal structures.

A small fraction of histones, more specifically, the amino side chainsthereof, are enzymatically modified by post-translational addition ofmethyl, acetyl, or phosphate groups, neutralising the positive charge ofthe side chain, or converting it to a negative charge. For example,lysine and arginine groups may be methylated, lysine groups may beacetylated, and serine groups may be phosphorylated. For lysine, the—(CH₂)₄—NH₂ sidechain may be acetylated, for example by anacetyltransferase enzyme, to give the amide —(CH₂)₄—NHC(═O)CH₃.Methylation, acetylation, and phosphorylation of amino termini ofhistones which extend from the nucleosomal core affects chromatinstructure and gene expression. (See, for example, Spencer and Davie,1999).

Acetylation and deacetylation of histones is associated withtranscriptional events leading to cell proliferation and/ordifferentiation. Regulation of the function of transcription factors isalso mediated through acetylation. Recent reviews of histonedeacetylation include Kouzarides, 1999 and Pazin et al., 1997.

The correlation between the acetylation status of histones and thetranscription of genes has been known for over 30 years (see, forexample, Howe et al., 1999). Certain enzymes, specifically acetylases(e.g., histone acetyltransferase, HAT) and deacetylases (e.g., histonedeacetylase, HDAC), which regulate the acetylation state of histoneshave been identified in many organisms and have been implicated in theregulation of numerous genes, confirming the link between acetylationand transcription. See, for example, Davie, 1998. In general, histoneacetylation correlates with transcriptional activation, whereas histonedeacetylation is associated with gene repression.

A growing number of histone deacetylases (HDACs) have been identified(see, for example, Ng and Bird, 2000). The first deacetylase, HDAC1, wasidentified in 1996 (see, for example, Tauton et al., 1996).Subsequently, two other nuclear mammalian deacetylases were found, HDAC2and HDAC3 (see, for example, Yang et al., 1996, 1997, and Emiliani etal., 1998). See also, Grozinger et al., 1999; Kao et al., 2000; and Vanden Wyngaert et al., 2000.

Eleven (11) human HDACs have been cloned so far:

-   -   HDAC1 (Genbank Accession No. NP_(—)004955)    -   HDAC2 (Genbank Accession No. NP_(—)001518)    -   HDAC3 (Genbank Accession No. O15379)    -   HDAC4 (Genbank Accession No. AAD29046)    -   HDAC5 (Genbank Accession No. NP_(—)005465)    -   HDAC6 (Genbank Accession No. NP_(—)006035)    -   HDAC7 (Genbank Accession No. AAF63491)    -   HDAC8 (Genbank Accession No. AAF73428)    -   HDAC9 (Genbank Accession No. AAK66821)    -   HDAC10 (Genbank Accession No. AAK84023)    -   HDAC11 (Genbank Accession No. NM_(—)024827

These eleven human HDACs fall in two distinct classes: HDACs 1, 2, 3 and8 are in class I, and HDACs 4, 5, 6, 7, 9, 10 and 11 are in class II.

There are a number of histone deacetylases in yeast, including thefollowing:

-   -   RPD3 (Genbank Accession No. NP_(—)014069)    -   HDA1 (Genbank Accession No. P53973)    -   HOS1 (Genbank Accession No. Q12214)    -   HOS2 (Genbank Accession No. P53096)    -   HOS3 (Genbank Accession No. Q02959)

There are also numerous plant deacetylases, for example, HD2, in Zeamays (Genbank Accession No. AF254073_(—)1).

HDACs function as part of large multiprotein complexes, which aretethered to the promoter and repress transcription. Well characterisedtranscriptional repressors such as Mad (Laherty et al., 1997), pRb(Brehm et al., 1998), nuclear receptors (Wong et al., 1998) and YY1(Yang et al., 1997) associate with HDAC complexes to exert theirrepressor function.

The study of inhibitors of histone deacetylases indicates that theseenzymes play an important role in cell proliferation anddifferentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al.,1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida andBeppu, 1988), reverts the transformed phenotype of different cell lines,and induces differentiation of Friend leukaemia cells and others(Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibitcell growth, induce terminal differentiation, and prevent the formationof tumours in mice (Finnin et al., 1999).

Cell cycle arrest by TSA correlates with an increased expression ofgelsolin (Hoshikawa et al., 1994), an actin regulatory protein that isdown regulated in malignant breast cancer (Mielnicki et al., 1999).Similar effects on cell cycle and differentiation have been observedwith a number of deacetylase inhibitors (Kim et al., 1999).

Trichostatin A has also been reported to be useful in the treatment offibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts etal., 1998.

Recently, certain compounds that induce differentiation have beenreported to inhibit histone deacetylases. Several experimentalantitumour compounds, such as trichostatin A (TSA), trapoxin,suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have beenreported to act, at least in part, by inhibiting histone deacetylase(see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al.,1993). Additionally, diallyl sulfide and related molecules (see, e.g.,Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999; Sonoda etal., 1996), MS-27-275, a synthetic benzamide derivative (see, e.g.,Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was laterre-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan,1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see,e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide(see, e.g., Richon et al., 1998) have been reported to inhibit histonedeacetylases. In vitro, some of these compounds are reported to inhibitthe growth of fibroblast cells by causing cell cycle arrest in the G1and G2 phases, and can lead to the terminal differentiation and loss oftransforming potential of a variety of transformed cell lines (see,e.g., Richon et al., 1996; Kim et al., 1999; Yoshida et al., 1995;Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to beeffective in the treatment of acute promyelocytic leukemia inconjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHAis reported to be effective in preventing the formation of mammarytumours in rats, and lung tumours in mice (see, e.g., Desai et al.,1999).

The clear involvement of HDACs in the control of cell proliferation anddifferentiation suggests that aberrant HDAC activity may play a role incancer. The most direct demonstration that deacetylases contribute tocancer development comes from the analysis of different acutepromyelocytic leukemias (APL). In most APL patients, a translocation ofchromosomes 15 and 17 (t(15;17)) results in the expression of a fusionprotein containing the N-terminal portion of PML gene product linked tomost of RARα (retinoic acid receptor). In some cases, a differenttranslocation (t(11;17)) causes the fusion between the zinc fingerprotein PLZF and RARα. In the absence of ligand, the wild type RARαrepresses target genes by tethering HDAC repressor complexes to thepromoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARαand displaces the repressor complex, allowing expression of genesimplicated in myeloid differentiation. The RARα fusion proteinsoccurring in APL patients are no longer responsive to physiologicallevels of RA and they interfere with the expression of the RA-induciblegenes that promote myeloid differentiation. This results in a clonalexpansion of promyelocytic cells and development of leukaemia. In vitroexperiments have shown that TSA is capable of restoringRA-responsiveness to the fusion RARα proteins and of allowing myeloiddifferentiation. These results establish a link between HDACs andoncogenesis and suggest that HDACs are potential targets forpharmaceutical intervention in APL patients. (See, for example, Kitamuraet al., 2000; David et al., 1998; Lin et al., 1998).

Furthermore, different lines of evidence suggest that HDACs may beimportant therapeutic targets in other types of cancer. Cell linesderived from many different cancers (prostate, colorectal, breast,neuronal, hepatic) are induced to differentiate by HDAC inhibitors(Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have beenstudied in animal models of cancer. They reduce tumour growth andprolong the lifespan of mice bearing different types of transplantedtumours, including melanoma, leukaemia, colon, lung and gastriccarcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).

Psoriasis is a common chronic disfiguring skin disease which ischaracterised by well-demarcated, red, hardened scaly plaques: these maybe limited or widespread. The prevalence rate of psoriasis isapproximately 2%, i.e., 12.5 million sufferers in the triad countries(US/Europe/Japan). While the disease is rarely fatal, it clearly hasserious detrimental effects upon the quality of life of the patient:this is further compounded by the lack of effective therapies. Presenttreatments are either ineffective, cosmetically unacceptable, or possessundesired side effects. There is therefore a large unmet clinical needfor effective and safe drugs for this condition.

Psoriasis is a disease of complex etiology. Whilst there is clearly agenetic component, with a number of gene loci being involved, there arealso undefined environmental triggers. Whatever the ultimate cause ofpsoriasis, at the cellular level, it is characterised by local T-cellmediated inflammation, by keratinocyte hyperproliferation, and bylocalised angiogenesis. These are all processes in which histonedeacetylases have been implicated (see, e.g., Saunders et al., 1999;Bernhard et al., 1999; Takahashi et al., 1996; Kim et al, 2001).Therefore HDAC inhibitors may be of use in therapy for psoriasis.Candidate drugs may be screened, for example, using proliferation assayswith T-cells and/or keratinocytes.

Thus, one aim of the present invention is the provision of compoundswhich are potent inhibitors of histone deacetylases (HDACs). There is apressing need for such compounds, particularly for use asantiproliferatives, for example, anti-cancer agents, agents for thetreatment of psoriasis, etc.

Such molecules desirably have one or more of the following propertiesand/or effects:

-   -   (a) easily gain access to and act upon tumour cells;    -   (b) down-regulate HDAC activity;    -   (c) inhibit the formation of HDAC complexes;    -   (d) inhibit the interactions of HDAC complexes;    -   (e) inhibit tumour cell proliferation;    -   (e) promote tumour cell apoptosis;    -   (f) inhibit tumour growth; and,    -   (g) complement the activity of traditional chemotherapeutic        agents.

A number of carbamic acid compounds have been described.

Certain classes of carbamic acid compounds which inhibit HDAC aredescribed in Watkins et al., 2002a, 2002b, and 2002c.

Piperazino Amides

Alpegiani et al., 1999, describe compounds of the following type (Q² hasbackbone=2; is alkylene; is α-substituted) which are proposed to beuseful in the treatment of diseases involving matrix metalloproteases(MMPs) and/or tumor necrosis factor α (TNF-α).

Alpegiani et al., 1999, also describes the following compound (Q² hasbackbone=2; is alkylene; is α-substituted):

Billedeau et al., 2000, describe compounds of the following type(wherein R¹ is, e.g., phenyl) (Q² has backbone=3; is alkylene; isα-substituted), which apparently inhibit procollagen C-proteinase, andare proposed for use in the treatment of fibrotic diseases.

Broadhurst et al., 1993, describe the following compound (Q² hasbackbone=2; is alkylene; is α-substituted), which apparently inhibitscollagenase.

Broadhurst et al., 1995, describe the following compound (Q² hasbackbone=2; is alkylene; is α-substituted), which apparently inhibitscollagenase, and is proposed for use in the treatment of cancer,arteriosclerosis and inflammation.

Hou et al., 2001, describe the following compound (Q² has backbone=2; isalkylene; is α-substituted), which apparently inhibits the proteinasegelatinase-A.

Owen et al., 2001, describe the following compound (Q² has backbone=2;is alkylene), which apparently inhibits certain MMPs, and is proposedfor use in the treatment of inflammation.

Pratt et al., 2001, describe the following compounds (Q² has backbone=2;is alkylene), which apparently have anti-bacterial activity.

Piperazino Bisamides

A number of hydroxamic acids comprising a piperazine moiety withcarbonyl groups adjacent to each nitrogen atom of the piperazine moietyare known.

Chong et al., 2002 describe the following compound (Q² has backbone=2;is alkylene) as an inhibitor of peptide deformylase for use as anantibiotic.

Billedeau et al., 2000 describe the following two compounds (Q² hasbackbone=3; is alkylene; is α-substituted) as inhibitors of procollagenC-proteinase for use in the treatment of fibrosis, sclerosis, arthritisand acute respiratory distress syndrome.

Piperazino Sulfonamides

Barlaam et al., 2000, describe compounds of the following type (whereinR³ may be, e.g., phenyl) (Q² has backbone=2; is alkylene; is optionallyβ-substituted), which apparently inhibit MMP-13.

Two examples of such compounds (Q² has backbone=2; is alkylene) includethe following.

Barlaam et al., 2001, describe compounds of the following type (Q² hasbackbone=2; is alkylene) which apparently inhibit MMP-13 and collagenase3.

Barta et al., 2000, describe the following compound (Q² has backbone=2;is phenylene), which apparently inhibits MMP-2 and MMP-13.

Baxter et al., 1999, (Darwin Discovery, UK) describe the followingcompound (Q² has backbone=2; is alkylene), which apparently inhibitscertain MMPs.

Baxter et al., 2000, (Darwin Discovery, UK) describe compounds of thefollowing type (Q² has backbone=2; is alkylene), which apparentlyinhibitor certain MMPs.

Bedell et al., 2000, and Bedell et al., 2001, describe compounds of thefollowing type (Q² has backbone=2; is phenylene), which apparentlyinhibit certain MMPs.

De Crescenzo et al., 2000, describe compounds of the following type (Q²has backbone=2; is alkylene), which apparently inhibit certain MMPs.

Hannah et al., 2001, (Darwin Discovery, UK) describe compounds of thefollowing type (Q² has backbone=2; is alkylene; is optionallyα-substituted), which apparently inhibit certain MMPs.

Martin et al., 2000, describes the following compound (Q² hasbackbone=2; is alkylene), which apparently inhibits certain MMPs.

Owen et al., 2000, (Darwin Discovery, UK) describe compounds of thefollowing type (Q² has backbone=2; is phenylene), which are apparentlyinhibit certain MMPs.

Owen et al., 2000, (Darwin Discovery, UK) also describes the followingcompound (Q² has backbone=3; is phenylene):

SUMMARY OF THE INVENTION

One aspect of the invention pertains to active carbamic acid compounds,as described herein.

Another aspect of the invention pertains to active compounds, asdescribed herein, which inhibit HDAC activity.

Another aspect of the invention pertains to active compounds, asdescribed herein, which treat conditions which are known to be mediatedby HDAC, or which are known to be treated by HDAC inhibitors (such as,e.g., trichostatin A).

Another aspect of the invention pertains to active compounds, asdescribed herein, which (a) regulate (e.g., inhibit) cell proliferation;(b) inhibit cell cycle progression; (c) promote apoptosis; or (d) acombination of one or more of these.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are anti-HDAC agents, and which treat acondition mediated by HDAC.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are anticancer agents, and which treat cancer.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are antiproliferative agents, and which treat aproliferative condition.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are antipsoriasis agents, and which treatpsoriasis.

Another aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a carrier.

Another aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a pharmaceuticallyacceptable carrier.

Another aspect of the present invention pertains to methods ofinhibiting HDAC in a cell, comprising contacting said cell with aneffective amount of an active compound, as described herein, whether invitro or in vivo.

Another aspect of the present invention pertains to methods of (a)regulating (e.g., inhibiting) cell proliferation; (b) inhibiting cellcycle progression; (c) promoting apoptosis; or (d) a combination of oneor more of these, comprising contacting a cell with an effective amountof an active compound, as described herein, whether in vitro or in vivo.

Another aspect of the present invention pertains to methods of treatinga condition which is known to be mediated by HDAC, or which is known tobe treated by HDAC inhibitors (such as, e.g., trichostatin A),comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to methods of treatingcancer, comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to methods of treatinga proliferative condition comprising administering to a subject in needof treatment a therapeutically-effective amount of an active compound,as described herein.

Another aspect of the present invention pertains to methods of treatingpsoriasis comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to an active compound,as described herein, for use in a method of treatment of the human oranimal body by therapy.

Another aspect of the present invention pertains to use of an activecompound, as described herein, for the manufacture of a medicament foruse in the treatment of a condition mediated by HDAC, a condition knownto be treated by HDAC inhibitors (such as, e.g., trichostatin A),cancer, a proliferative condition, psoriasis, or other condition asdescribed herein.

Another aspect of the present invention pertains to a kit comprising (a)the active compound, preferably provided as a pharmaceutical compositionand in a suitable container and/or with suitable packaging; and (b)instructions for use, for example, written instructions on how toadminister the active compound.

Another aspect of the present invention pertains to compounds obtainableby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to compounds obtainedby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION Compounds

In one aspect, the present invention pertains to carbamic acid compoundsof the formula:

wherein:

-   -   Cy is independently a cyclyl group;    -   Q¹ is independently a covalent bond or cyclyl leader group;    -   the piperazin-1,4-diyl group is optionally substituted;    -   J¹ is independently a covalent bond or —C(═O)—;    -   J² is independently —C(═Of or —S(═O)₂—;    -   Q² is independently an acid leader group;        wherein:    -   Cy is independently:        -   C₃₋₂₀carbocyclyl,        -   C₃₋₂₀heterocyclyl, or        -   C₅₋₂₀aryl;        -   and is optionally substituted;    -   Q¹ is independently:        -   a covalent bond;        -   C₁₋₇alkylene; or        -   C₁₋₇alkylene-X—C₁₋₇alkylene, —X—C₁₋₇alkylene, or            C₁₋₇alkylene-X—,        -   wherein X is —O— or —S—;        -   and is optionally substituted;    -   Q² is independently:        -   C₄₋₆alkylene;        -   and is optionally substituted;        -   and has a backbone length of at least 4 atoms;    -   or:    -   Q² is independently:        -   C₅₋₂₀arylene;        -   C₅₋₂₀arylene-C₁₋₇alkylene;        -   C₁₋₇alkylene-C₁₋₂₀arylene; or,        -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;        -   and is optionally substituted;        -   and has a backbone length of at least 4 atoms;            and pharmaceutically acceptable salts, solvates, amides,            esters, ethers, chemically protected forms, and prodrugs            thereof.

In preferred embodiments, the carbamic acid group, —C(═O)NHOH, isunmodified (e.g., is not an ester).

Note that each of the groups -J¹-Q¹-Cy and -J²-Q²-C(═O)NHOH is amonovalent and monodentate species; and that is it not intended thatthese groups be linked, other than via the N-1 and N-4 atoms,respectively, of the piperazin-1,4-diyl group.

The Piperazin-1,4-diyl Group

The piperazin-1,4-diyl group is optionally substituted, i.e.,unsubstituted or substituted.

In one embodiment, the piperazin-1,4-diyl group is unsubstituted (i.e.,unsubstituted at the 2-, 3-, 5-, and 6-positions).

In one embodiment, the piperazin-1,4-diyl group is substituted (i.e.,substituted at one or more the 2-, 3-, 5-, and 6-positions.

For example, in one embodiment, the piperazin-1,4-diyl group issubstituted (i.e., substituted at one or more the 2-, 3-, 5-, and6-positions with C₁₋₄alkyl, for example, -Me or -Et.

For example, in one embodiment, the piperazin-1,4-diyl group is:unsubstituted piperazin-1,4-diyl or 2-methyl-piperazin-1,4-diyl.

The piperazin-1,4-diyl group may be in any conformation, including, butnot limited to, chair-, boat-, or twist-forms.

The Linkers, J¹ and J²

In one embodiment, J¹ is independently a covalent bond.

In one embodiment, J¹ is independently —C(═O)—.

In one embodiment, J² is independently —C(═O)—.

In one embodiment, J² is independently —S(═O)₂—.

In one embodiment:

J¹ is a covalent bond and J² is —C(═O); or:

J¹ is —C(═O)— and J² is —C(═O)—; or:

J¹ is a covalent bond and J² is —S(═O)₂—.

In one embodiment:

J¹ is a covalent bond and J² is —C(═O)—; or:

J¹ is —C(═O)— and J² is —C(═O)—.

In one embodiment, J¹ is a covalent bond and J² is —C(═O)— (and thecompounds may be referred to as “piperazino-amides”):

In one embodiment, J¹ is —C(═O)— and J² is —C(═O)— (and the compoundsmay be referred to as “piperazino-bisamides”):

In one embodiment, J¹ is a covalent bond and J² is —S(═O)₂— (and thecompounds may be referred to as “piperazino-sulfonamides”):

In one embodiment, J¹ is —C(═O)— and J² is —S(═O)₂— (and the compoundsmay be referred to as “piperazino-amide-sulfonamides”):

For the avoidance of doubt, it is intended that, if there is a —C(═O)—group immediately adjacent to the N-1 atom of the piperazin-1-4-diylgroup, then that —C(═O)— group must be assigned as J¹ (that is, J¹ is—(C═O)—) and not as part of Q¹ (e.g., as part of an oxo-substituted Q¹group). For example, if the Cy-Q¹-J¹- group is Ph-CH₂—C(═O)—, then Cy isPh-, Q¹ is —CH₂—, and J¹ is —C(═O)—.

Assigning the Cyclyl Group, Cy

If, within the group -J¹-Q¹-Cy, there is a plurality of candidate groupssatisfying the definition of Cy (referred to as candidate Cy groups),then the candidate Cy group which is furthest from the N-1 atom of thepiperazin-1,4-diyl group is identified as Cy (and referred to as “therelevant Cy group”).

In this context, distance (e.g., further, furthest) is measured as thenumber of chain atoms in the shortest continuous chain linking thegroups (i.e., the N-1 atom and Cy).

If there is a plurality of furthest candidate Cy groups, then the one(including any substituents) with the largest molecular weight is therelevant one.

If there is a plurality of furthest heaviest candidate Cy groups, thenthe one (excluding any substituents) with the most annular heteroatomsis the relevant one.

If there is a plurality of furthest heaviest candidate Cy groups withthe most annular heteroatoms, then the one with an IUPAC name whichalphabetically precedes the other(s), is the relevant one.

Some illustrative examples are shown below.

If the group, Q¹, is a cyclyl leader group (i.e., not a covalent bond)and/or J1 is —C(═O)—, the group -Q¹-J¹- has a backbone length, asdetermined by the number of chain atoms in the shortest continuous chainof atoms linking the relevant cyclyl group, Cy, and the N-1 atom of thepiperazin-1,4-diyl group. In the following example, -Q¹-J¹- has abackbone length of 2.

The Cyclyl Group, Cy

Cy is independently: C₃₋₂₀carbocyclyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl;and is optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀carbocyclyl; and isoptionally substituted.

In one embodiment, Cy is independently monocyclic C₃₋₇carbocyclyl, andis optionally substituted.

In one embodiment, Cy is independently monocyclic C₅₋₆carbocyclyl, andis optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀carbocyclyl derived from oneof the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane,cyclopentene, cyclohexene, norbornane, adamantane, cyclopentanone, andcyclohexanone; and is optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀heterocyclyl; and isoptionally substituted.

In one embodiment, Cy is independently monocyclic C₃₋₇heterocyclyl, andis optionally substituted.

In one embodiment, Cy is independently monocyclic C₅₋₆heterocyclyl, andis optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀heterocyclyl derived fromone of the following: piperidine, azepine, tetrahydropyran, morpholine,azetidine, piperazine, imidazoline, piperazinedione, and oxazolinone;and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀aryl; and is optionallysubstituted.

In one embodiment, Cy is independently C₅₋₂₀carboaryl orC₅₋₂₀heteroaryl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀heteroaryl; and isoptionally substituted. In one embodiment, Cy is monocyclicC₅₋₂₀heteroaryl; and is optionally substituted. In one embodiment, Cy ismonocyclic C₅₋₆heteroaryl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀carboaryl; and is optionallysubstituted. In one embodiment, Cy is monocyclic C₅₋₂₀carboaryl; and isoptionally substituted. In one embodiment, Cy is monocyclicC₅₋₆carboaryl; and is optionally substituted. In one embodiment, Cy isphenyl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀aryl derived from one of thefollowing: benzene, pyridine, furan, indole, pyrrole, imidazole,pyrimidine, pyrazine, pyridizine, naphthalene, quinoline, indole,benzimidazole, benzothiofuran, fluorene, acridine, and carbazole; and isoptionally substituted.

Examples of substituents on Cy include, but are not limited to, thosedescribed under the heading “Substituents” below.

In one embodiment, the optional substituents on Cy are as defined underthe heading “The Cyclyl Group, Cy: Optionally Substituted Phenyl:Substituents.”

The Cyclyl Group, Cy: Optionally Substituted Phenyl

In one embodiment, Cy is independently an optionally substituted phenylgroup.

In one embodiment, Cy is independently an optionally substituted phenylgroup of the formula:

wherein n is independently an integer from 0 to 5, and each R^(A) isindependently a substituent as defined herein.

In one embodiment, Cy is an optionally substituted phenyl group, Q¹ is acovalent bond or a cyclyl leader group, J¹ is a covalent bond, and thecompounds have the following formula:

In one embodiment, Cy is an optionally substituted phenyl group, Q¹ is acyclyl leader group, J¹ is a covalent bond, and the compounds have thefollowing formula:

In one embodiment, Cy is an optionally substituted phenyl group, Q¹ is acovalent bond, J¹ is a covalent bond, and the compounds have thefollowing formula:

In one embodiment, n is an integer from 0 to 5.

In one embodiment, n is an integer from 0 to 4.

In one embodiment, n is an integer from 0 to 3.

In one embodiment, n is an integer from 0 to 2.

In one embodiment, n is 0 or 1.

In one embodiment, n is an integer from 1 to 5.

In one embodiment, n is an integer from 1 to 4.

In one embodiment, n is an integer from 1 to 3.

In one embodiment, n is 1 or 2.

In one embodiment, n is 5.

In one embodiment, n is 4.

In one embodiment, n is 3.

In one embodiment, n is 2.

In one embodiment, n is 1.

In one embodiment, n is 0.

If the phenyl group has less than the full complement of ringsubstituents, R^(A), they may be arranged in any combination. Forexample, if n is 1, R^(A) may be in the 2′-, 3′-, 4′-, 5′-, or6′-position. Similarly, if n is 2, the two R^(A) groups may be in, forexample, the 2′,3′-, 2′,4′-, 2′,5′-, 2′,6′-, 3′,4′-, or 3′,5′-positions.If n is 3, the three R^(A) groups may be in, for example, the 2′,3′,4′-,2′,3′,5′-, 2′,3′,6′-, or 3′,4′,5′-positions.

In one embodiment, n is 0.

In one embodiment, n is 1, and the R^(A) group is in the 4′-position.

In one embodiment, n is 2, and one R^(A) group is in the 4′-position,and the other R^(A) group is in the 2′-position.

In one embodiment, n is 2, and one R^(A) group is in the 4′-position,and the other R^(A) group is in the 3′-position.

The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents

Examples of substituents on Cy (e.g., R^(A)), include, but are notlimited to, those described under the heading “Substituents” below.

Further examples of substituents on Cy (e.g., R^(A)), include, but arenot limited to, those described below.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

(1) ester;

(2) amido;

(3) acyl;

(4) halo;

(5) hydroxy;

(6) ether;

(7) C₁₋₇alkyl, including substituted C₁₋₇alkyl;

(8) C₅₋₂₀aryl, including substituted C₅₋₂₀aryl;

(9) sulfonyl;

(10) sulfonamido;

(11) amino;

(12) morpholino;

(13) nitro;

(14) cyano.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

(1) —C(═O)OR¹, wherein R¹ is independently C₁₋₇alkyl as defined in (7);

(2) —C(═O)NR²R³, wherein each of R² and R³ is independently —H orC₁₋₇alkyl as defined in (7);

(3) —C(═O)R⁴, wherein R⁴ is independently C₁₋₇alkyl as defined in (7) orC₅₋₂₀aryl as defined in (8);

(4) —F, —Cl, —Br, —I;

(5) —OH;

(6) —OR⁵, wherein R⁵ is independently C₁₋₇alkyl as defined in (7) orC₅₋₂₀aryl as defined in (8);

(7) C₁₋₇alkyl, including substituted C₁₋₇alkyl, e.g.,

-   -   halo-C₁₋₇alkyl;    -   amino-C₁₋₇alkyl (e.g., —(CH₂)_(w)-amino);    -   carboxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—COOH);    -   hydroxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—OH);    -   C₁₋₇alkoxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—O—C₁₋₇alkyl);    -   C₅₋₂₀aryl-C₁₋₇alkyl;    -   wherein w is 1, 2, 3, or 4;        (8) C₅₋₂₀aryl, including substituted C₅₋₂₀aryl;        (9) —SO₂R⁷, wherein R⁷ is independently C₁₋₇alkyl as defined        in (7) or C₅₋₂₀aryl as defined in (8);        (10) —SO₂NR⁸R⁹, wherein each of R⁸ and R⁹ is independently —H or        C₁₋₇alkyl as defined in (7);        (11) —NR¹⁰R¹¹, wherein each of R¹⁰ and R¹¹ is independently —H        or C₁₋₇ alkyl as defined in (7);        (12) morpholino;        (13) nitro;        (14) cyano.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

(1) —C(═O)OMe, —C(═O)OEt, —C(═O)O(Pr), —C(═O)O(iPr), —C(═O)O(nBu),—C(═O)O(sBu), —C(═O)O(iBu), —C(═O)O(tBu), —C(═O)O(nPe); —C(═O)OCH₂CH₂OH,—C(═O)OCH₂CH₂OMe, —C(═O)OCH₂CH₂OEt;

(2) —(C═O)NH₂, —(C═O)NMe₂, —(C═O)NEt₂, —(C═O)N(iPr)₂,—(C═O)N(CH₂CH₂OH)₂;

(3) —(C═O)Me, —(C═O)Et, —(C═O)-cHex, —(C═O)Ph;

(4) —F, —Cl, —Br, —I;

(5) —OH;

(6) —OMe, —OEt, —O(iPr), —O(tBu), —OPh;

—OCF₃, —OCH₂CF₃;

—OCH₂CH₂OH, —OCH₂CH₂OMe, —OCH₂CH₂OEt;

—OCH₂CH₂NH₂, —OCH₂CH₂NMe₂, —OCH₂CH₂N(iPr)₂;

—OPh, —OPh-Me, —OPh-OH, —OPh-OMe, O-Ph-F, —OPh-Cl, —OPh-Br, —OPh-I;

(7) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;

—CF₃, —CH₂CF₃;

—CH₂CH₂OH, —CH₂CH₂OMe, —CH₂CH₂OEt;

—CH₂CH₂NH₂, —CH₂CH₂NMe₂, —CH₂CH₂N(iPr)₂;

—CH₂-Ph;

(8) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I;

(9) —SO₂Me, —SO₂Et, —SO₂Ph;

(10) —SO₂NH₂, —SO₂NMe₂, —SO₂NEt₂;

(11) —NMe₂, —NEt₂;

(12) morpholino;

(13) —NO₂;

(14) —CN.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

—C(═O)OMe, —C(═O)O(Pr), —C(═O)NHMe, —C(═O)Et, C(═O)Ph, —OCH₂CH₂OH, —OMe,—OPh,

-nPr, iPr, —CF₃, —CH₂CH₂OH, —CH₂CH₂NMe₂,

-Ph, -Ph-F, -Ph-Cl,

—SO₂Me, —SO₂Me₂, —NMe₂,

—F, —Cl, -Me, -Et, —OMe, —OEt, —CH₂-Ph, —O—CH₂-Ph.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

—F, —Cl, -Me, -Et, —OMe, —OEt, -Ph, —OPh, —CH₂-Ph, —O—CH₂-Ph.

Examples of some preferred substituents on Cy (e.g., R^(A)), include,but are not limited to, the following: fluoro, chloro, bromo, iodo,methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy,methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio,trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino,morpholino, amido (unsubstituted, i.e., —CONH₂), acetamido, acetyl,nitro, sulfonamido (unsubstituted, i.e., —SO₂NH₂), and phenyl.

The Cyclyl Leader Group, Q¹

In one embodiment, Q¹ is independently:

-   -   a covalent bond; or    -   a cyclyl leader group;    -   and is optionally substituted.

In one embodiment, Q¹ is independently:

-   -   a covalent bond.

In one embodiment, Q¹ is independently:

-   -   a cyclyl leader group;    -   and is optionally substituted.

In one embodiment, Q¹ is independently:

-   -   a covalent bond;    -   C₁₋₇alkylene; or    -   C₁₋₇alkylene-X—C₁₋₇alkylene, —X—C₁₋₇alkylene, or        C₁₋₇alkylene-X—;    -   wherein X is —O— or —S—;    -   and is optionally substituted.

In one embodiment, Q¹ is independently:

-   -   a covalent bond; or    -   a C₁₋₇alkylene group;    -   and is optionally substituted.

In one embodiment, Q¹ is independently:

-   -   a C₁₋₇alkylene group;    -   and is optionally substituted.

In one embodiment, Q¹ is independently:

-   -   C₁₋₇alkylene-X—C₁₋₇alkylene, —X—C₁₋₇alkylene, or        C₁₋₇alkylene-X—;    -   wherein X is —O— or —S—;    -   and is optionally substituted.

In one embodiment, in the above alkylene groups, each alkylene group isindependently:

(a) a saturated C₁₋₇alkylene group; or:

(b) a partially unsaturated C₂₋₇alkylene group; or:

(c) an aliphatic C₁₋₇alkylene group; or:

(d) a linear C₁₋₇alkylene group; or:

(e) a branched C₂₋₇alkylene group; or:

(f) a saturated aliphatic C₁₋₇alkylene group; or:

(g) a saturated linear C₁₋₇alkylene group; or

(h) a saturated branched C₂₋₇alkylene group; or

(i) a partially unsaturated aliphatic C₂₋₇alkylene group; or:

(j) a partially unsaturated linear C₂₋₇alkylene group; or:

(k) a partially unsaturated branched C₂₋₇alkylene group;

and is optionally substituted.

In one embodiment, the above alkylene groups have a maximum number ofcarbon atoms of 4, e.g., C₁₋₄alkylene, C₂₋₄alkylene.

In one embodiment, the above alkylene groups have a maximum number ofcarbon atoms of 3, e.g., C₁₋₃alkylene, C₂₋₃alkylene.

In one embodiment, Q′ is selected so that the N-1 atom of thepiperazin-1,4-diyl group is not connected to a carbon atom which isconnected to another carbon atom via a non-aromatic carbon-carbon doublebond (i.e., C═C). That is, the N-1 atom of the piperazin-1,4-diyl groupis not adjacent to a non-aromatic carbon-carbon double bond (i.e., C═C).In this way, groups such as —CH═CH— and —CH₂—CH═CH— are excluded fromQ¹, but groups such as —CH═CH—CH₂— are not. Additional embodimentsinclude other embodiments described herein (e.g., those described above)further limited by this restriction upon Q¹.

The Cyclyl Leader Group, Q¹: Covalent Bond

In one embodiment:

-   -   Q¹ is independently a covalent bond;    -   J¹ is independently a covalent bond;    -   J² is independently —C(═O)—.

In one embodiment:

-   -   Q¹ is independently a covalent bond;    -   J¹ is independently —C(═O)—;    -   J² is independently —C(═O)—.

In one embodiment:

-   -   Q¹ is independently a covalent bond;    -   J¹ is independently a covalent bond;    -   J² is independently —S(═O)₂—.

In one embodiment:

-   -   Q¹ is independently a covalent bond;    -   J¹ is independently —C(═O)—;    -   J² is independently —S(═O)₂—.        The Cyclyl Leader Group, Q¹: Backbone Length

The group -J¹-Q¹- has a backbone length, as determined by the number ofchain atoms in the shortest continuous chain of atoms linking therelevant Cy group and the N-1 atom of the piperazin-1,4-diyl group.

In one embodiment, the group -J¹-Q¹- has a backbone of:

from 1 to 7 atoms;

from 1 to 6 atoms;

from 1 to 5 atoms;

from 1 to 4 atoms; or,

from 1 to 3 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of at least 2 atoms.In this way, groups such as methylene (—CH₂—) and substituted methylene(—CR₂— and —CHR—) are excluded.

In one embodiment, the group -J¹-Q¹- has a backbone of at least 3 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of at least 4 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of at least 5 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of:

from 2 to 7 atoms;

from 2 to 6 atoms; or,

from 2 to 5 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of:

from 3 to 7 atoms;

from 3 to 6 atoms; or,

from 3 to 5 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of:

from 4 to 7 atoms;

from 4 to 6 atoms; or,

from 4 to 5 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of 1 atom.

In one embodiment, the group -J¹-Q¹- has a backbone of 2 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of 3 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of 4 atoms.

In one embodiment, the group -J¹-Q¹- has a backbone of 5 atoms.

In one embodiment, the backbone of “atoms” is a backbone of “carbonatoms.”

Note that, for embodiments which are characterised by, or furthercharacterised by, a backbone length limitation, corresponding changes inthe description of that embodiment may be implicit. For example, for anembodiment wherein (a) Q¹ is a partially unsaturated C₂₋₇alkylene groupand (b) Q¹ has a backbone of 4 carbon atoms, the term “C₂₋₇alkylene”group is necessarily, and implicitly, interpreted as “C₄₋₇alkylene.”

The Cyclyl Leader Group, Q¹: Substituents

In one embodiment, Q¹, if other than a covalent bond, is unsubstituted.

In one embodiment, Q¹, if other than a covalent bond, is optionallysubstituted.

In one embodiment, Q¹, if other than a covalent bond, is substituted.

Examples of substituents on Q¹ include, but are not limited to, thosedescribed under the heading “Substituents” below.

In one embodiment, substituents on Q¹, if present, are as defined underthe heading “The Cyclyl Group, Cy: Optionally Substituted Phenyl:Substituents.”

In one embodiment, substituents on Q¹, if present, are independently:halo, hydroxy, ether (e.g., C₁₋₇alkoxy), C₅₋₂₀aryl, acyl, amino, amido,acylamido, or oxo.

In one embodiment, substituents on Q¹, if present, are independently:—F, —Cl, —Br, —I, —OH, —OMe, —OEt, —OPr, -Ph, —NH₂, —CONH₂, or ═O.

In one embodiment, substituents on Q¹, if present, are independently —OHor -Ph.

In one embodiment, substituents on Q¹, if present, are independently-Ph.

For example, in one embodiment, Q¹ is unsubstituted methylene, and is—CH₂—; in one embodiment, Q¹ phenyl (-Ph) substituted methylene, and is—CH(Ph)-.

For example, in one embodiment, Q¹ is unsubstituted ethylene, and is—CH₂—CH₂—; in one embodiment, Q¹ is oxo (═O) substituted ethylene, andis —C(═O)—CH₂—; in one embodiment, Q¹ is hydroxy (—OH) substitutedethylene, and is —CH(OH)—CH₂—; in one embodiment, Q¹ is phenyl (-Ph)substituted ethylene, and is —CH₂CH(Ph)-.

Again, for the avoidance of doubt, it is intended that, if there is a—C(═O)— group immediately adjacent to the N-1 atom, of thepiperazin-1-4-diyl group, then that —C(—O)— group must be assigned as J¹(that is, J¹ is —(C═O)—) and not as part of Q¹ (e.g., as part of anoxo-substituted Q¹ group). For example, if the Cy-Q¹-J¹- group isPh-CH₂—C(═O)—, then Cy is Ph-, Q¹ is —CH₂—, and J¹ is —C(═O)—.

The Cyclyl Leader Group, Q¹: Alkylene: Certain Embodiments

Note that, for embodiments excluding, e.g., a covalent bond, certainbackbone lengths, absence of adjacent carbon-carbon double bonds, etc.,it is to be understood that the corresponding species listed below aresimilarly excluded from the respective embodiments discussed below.

In one embodiment, Q¹ is independently selected from the following:

-   -   a covalent bond;    -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,        —(CH₂)₇—;    -   —CH(CH₃)—;    -   —CH(CH₃)CH₂—, —CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—,        —CH₂CH₂CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₃)—, —CH(CH₃)CH₂CH₂CH₂CH(CH₃);    -   —CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂—, —CH₂CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, —CH₂CH₂CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—,        —CH₂CH₂CH(CH₂CH₃)CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;    -   —CH═CH—;    -   —CH═CHCH₂—, —CH₂CH═CH—;    -   —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—,        —CH₂CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,        —CH₂CH₂CH₂CH═CHCH₂—, —CH₂CH₂CH₂CH₂CH═CH—;    -   —C(CH₃)═CH—, —CH═C(CH₃)—;    -   —C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—;    -   —CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, —CH₂CH═C(CH₃)—;    -   —CH═CHCH═CH—;    -   —CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, —CH═CHCH₂CH═CH—;    -   —CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, —CH═CHCH₂CH₂CH═CH—,        —CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, —CH₂CH₂CH═CHCH═CH—;    -   —C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—,        —CH═CHCH═C(CH₃)—;    -   —C≡C—;    -   —C≡CCH₂—, —CH₂C≡C—; —C≡CCH(CH₃)—, —CH(CH₃)C≡C—;    -   —C≡CCH₂CH₂—, —CH₂C≡CCH₂—, —CH₂CH₂C≡C—;    -   —C≡CCH(CH₃)CH₂—, —C≡CCH₂CH(CH₃)—;    -   —CH(CH₃)C≡CCH₂—, —CH₂C≡CCH(CH₃)—;    -   —CH(CH₃)CH₂C≡C—, —CH₂CH(CH₃)C≡C—;    -   —C≡CCH═CH—, —CH═CHC≡C—, —C≡CC≡C—;    -   —C≡CCH₂CH₂CH₂—, —CH₂CH₂CH₂C≡C—;    -   —C≡CCH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂C≡C—;    -   —C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, —CH═CHCH═CHC≡C—;    -   —C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, —C≡CCH═C(CH₃)—.

In one embodiment, Q′ is selected from:

-   -   a covalent bond;    -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH₂CH(CH₃)CH₂—, —CH₂CH₂CH₂CH₂CH(CH₃)—;    -   —CH═CH—;    -   —CH═CHCH₂—, —CH═C(Me)CH₂—;    -   —CH═CH—CH═CH—;    -   —CH═CH—CH═CHCH₂—, —CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH═CH—;    -   —C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—,        —CH═CHCH═C(CH₃)—;

In one embodiment, Q¹ is selected from:

-   -   a covalent bond;    -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,    -   —CH═CH—;    -   —CH═CHCH₂—, —CH═C(Me)CH₂—;    -   —CH═CH—CH═CH—;    -   —C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—,        —CH═CHCH═C(CH₃)—;    -   —CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH₂CH═CH—.

In one embodiment, Q¹ is independently selected from:

-   -   a covalent bond;    -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₆;    -   —CH═CHCH₂—;    -   —CH═C(Me)CH₂—; and,    -   —CH═CH—CH═CHCH₂—.

In one embodiment, Q¹ is independently selected from:

-   -   a covalent bond;    -   —CH₂—;    -   —CH₂CH₂—;    -   —CH₂CH₂CH₂—;    -   —CH═CHCH₂—;    -   —CH═C(Me)CH₂—; and,    -   —CH═CH—CH═CHCH₂—.

In one embodiment, Q¹ is independently selected from:

-   -   a covalent bond;    -   —CH₂—;    -   —CH(*Ph)-;    -   —CH₂CH₂—;    -   —CH(*Ph)CH₂—;    -   —CH₂CH(*Ph)-;    -   —CH₂CH₂CH₂—;    -   —CH═CHCH₂—;    -   —CH═C(Me)CH₂—; and,    -   —CH═CH—CH═CHCH₂—;        wherein * indicates that the group (e.g., Ph) is optionally        substituted with one or more substituents as defined above under        the heading “The Cyclyl Group, Cy: Optionally Substituted        Phenyl: Substituents.”        The Cyclyl Leader Group, Q¹: Ethers and Thioethers: Certain        Embodiments

Note that, for embodiments excluding, e.g., a covalent bond, certainbackbone lengths, absence of adjacent carbon-carbon double bonds, etc.,it is to be understood that the corresponding species listed below aresimilarly excluded from the respective embodiments discussed below.

In one embodiment, Q¹ is independently selected from the following:

-   -   —(CH₂)_(a)—X—(CH₂)_(b)—    -   wherein X is —O— or —S— and    -   a and b are each independently 1, 2, 3, 4, 5, 6, or 7;    -   and a+b is at least 1.

In one embodiment, Q¹ is independently selected from the following:

-   -   —O—(CH₂)_(a)—    -   —S—(CH₂)_(a)—    -   —(CH₂)_(a)—O—    -   —(CH₂)_(a)—S—    -   —(CH₂)_(a)—O—(CH₂)_(b)—    -   —(CH₂)_(a)—S—(CH₂)_(b)—    -   wherein a and b are each independently 1, 2, 3, 4, 5, 6, or 7.

In one embodiment, Q¹ is independently selected from the following:

-   -   —O—CH₂—; —O—CH₂CH₂—; —O—CH₂CH₂CH₂—;    -   —S—CH₂—; —S—CH₂CH₂—; —S—CH₂CH₂CH₂—;    -   —CH₂—O—; —CH₂CH₂—O—; —CH₂CH₂CH₂—O—;    -   —CH₂—S—; —CH₂CH₂—S—; —CH₂CH₂CH₂—S—;    -   —CH₂—O—CH₂—; —CH₂—O—CH₂CH₂—; —CH₂CH₂—O—CH₂—; and    -   —CH₂CH₂—O—CH₂CH₂—.        The Group -Q¹-J¹-: Certain Embodiments

In one embodiment, the group -Q¹-J¹- has a formula selected from:

-   -   —CH₂—;    -   —CH(*Ph)-;    -   —CH₂CH₂—;    -   —CH₂CH(*Ph)-;    -   —CH(*Ph)CH₂—;    -   —CH₂CH₂CH₂—;    -   —C(═O)—;    -   —CH₂—C(═O)—;    -   —CH(*Ph)C(═O)—;    -   —CH₂CH₂—C(═O)—;    -   —O—CH₂—;    -   —O—CH₂CH₂—;    -   —CH₂—O—;    -   —CH₂CH₂—O—; and,    -   —O—CH₂—C(═O)—.        wherein * indicates that the group (e.g., Ph) is optionally        substituted with one or more substituents as defined above under        the heading “The Cyclyl Group, Cy: Optionally Substituted Phenyl        Substituents.”        The Group Cy-Q¹-: Certain Embodiments

In one embodiment, the group Cy-Q¹- has a formula selected from:

-   -   *Ph-;    -   *Ph-CH₂—;    -   (*Ph)₂CH—;    -   *Ph-CH₂CH₂—;    -   (*Ph)₂-CH₂CH₂—;    -   *Ph-CH₂CH(*Ph)-;    -   *Ph-CH₂CH₂CH₂—;    -   *Ph-CH═CHCH₂—;    -   *Ph-CH═C(Me)CH₂;    -   *Ph-CH═CHCH═CHCH₂—;    -   (*pyrid-3-yl)-CH═CHCH₂—; and,    -   (*cyclohexyl)-CH₂CH₂—;        wherein * indicates that the group (e.g., Ph, pyrid-3-yl,        cyclohexyl) is optionally substituted with one or more        substituents as defined above under the heading “The Cyclyl        Group, Cy: Optionally Substituted Phenyl: Substituents.”

In one embodiment, * indicates that the group (e.g., Ph, pyrid-3-yl,cyclohexyl) is optionally substituted with one or more of: —F, —Cl, —Br,—I, —OH, —OMe, —OEt, —OPr, -Ph, —NH₂, and —CONH₂.

The Acid Leader Group, Q²

The acid leader group, Q², is independently:

-   -   C₄₋₈alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms;        or:    -   C₅₋₂₀arylene;    -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene; or,    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, the acid leader group, Q², is independently:

-   -   C₄₋₈alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, the acid leader group, Q², is independently:

-   -   C₅₋₂₀arylene;    -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; or,    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.        The Acid Leader Group, Q²: Backbone Length

The acid leader group, Q², has a backbone length, as determined by thenumber of chain atoms in the shortest continuous chain of atoms linkingthe N-4 atom of the piperazin-1,4-diyl group and the carbamic acidgroup, —C(═O)NHOH.

If Q² is alkylene, Q² necessarily has a backbone of at least 1 atom.Some examples are shown below.

If Q² is arylene, arylene-alkylene, alkylene-arylene,alkylene-arylene-alkylene, Q² necessarily has a backbone of at least 2atoms. Some examples are shown below.

Without wishing to be bound to any particular theory, it is believedthat Q² groups with shorter backbone lengths prevent or reduce theinteraction of the carbamic acid group (—C(═O)NHOH) with HDAC (or itscomplexes), and thereby reduce the compound's activity as an HDACinhibitor.

In one embodiment, Q² has a backbone of at least 4 atoms.

In one embodiment, Q² has a backbone of at least 5 atoms.

In one embodiment, Q² has a backbone of at least 6 atoms.

In one embodiment, Q² has a backbone of:

from 4 to 8 atoms;

from 4 to 7 atoms;

from 4 to 6 atoms; or,

from 4 to 5 atoms.

In one embodiment, Q² has a backbone of:

from 5 to 8 atoms; or

from 5 to 7 atoms; or

from 5 to 6 atoms.

In one embodiment, Q² has a backbone of from 5 to 6 atoms.

In one embodiment, Q² has a backbone of 4 atoms.

In one embodiment, Q² has a backbone of 5 atoms.

In one embodiment, Q² has a backbone of 6 atoms.

In one embodiment, Q² has a backbone of 7 atoms.

In one embodiment, Q² has a backbone of 8 atoms.

In one embodiment, the backbone of “atoms” is a backbone of “carbonatoms.”

Note that, for embodiments which are characterised by, or furthercharacterised by, a backbone length limitation, corresponding changes inthe description of that embodiment may be implicit. For example, for anembodiment wherein (a) Q² is a partially unsaturated C₂₋₄alkylene groupand (b) Q² has a backbone of 4 carbon atoms, the term “C₂₋₈alkylene”group is necessarily, and implicitly, interpreted as “C₄₋₈alkylene.”

The Acid Leader Group, Q²: Substitution

In one embodiment, Q² is unsubstituted.

In one embodiment, Q² is optionally substituted.

In one embodiment, Q² is substituted.

The backbone atoms of the acid leader group, Q², which link J and thecarbamic acid group (—C(═O)NHOH), are denoted α, β, γ, δ, etc., startingwith the backbone atom adjacent to the carbamic acid group. Someexamples are illustrated below.

Without wishing to be bound to any particular theory, it is believedthat groups (e.g., substituents), particularly bulky groups (e.g.,substituents), at the α-position, or at either or both of the α- andβ-positions, prevent or reduce the interaction of the carbamic acidgroup (—C(═O)NHOH) with HDAC (or its complexes), and thereby reduce thecompound's activity as an HDAC inhibitor.

In one embodiment, Q² is, additionally, unsubstituted at the α-position.

In one embodiment, Q² is, additionally, unsubstituted at the α-positionand unsubstituted at the β-position.

Note that, in some embodiments, Q² may have a non-linear alkylene group(for example, a branched alkylene) adjacent to the carbamic acid group.An example, wherein Q² is a branched saturated C₆-alkylene, having amethyl group at the α-position, is shown below. Although there is agroup (i.e., a methyl group) at the α-position, such compounds areunsubstituted at the α-position, because the α-methyl group itself isconsidered to be part of the unsubstituted Q². Another example, whereinQ² is a branched saturated C₆-alkylene, having an amino group at theα-position and a methyl group at the β-position, is shown below; suchcompounds are α-substituted, β-unsubstituted.

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, Q² is, additionally, unsubstitutedat the α-position.

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH₂— or ═CH— group adjacent to the carbamic acid group (that is, at theα-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH₂— group adjacent to the carbamic acid group (that is, at theα-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a═CH— group adjacent to the carbamic acid group (that is, at theα-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, Q² is, additionally, unsubstitutedat the α-position and unsubstituted at the β-position.

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH₂CH₂—, —CH═CH—, or —C≡C— group adjacent to the carbamic acid group(that is, at the α,β-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH₂CH₂— or —CH═CH— group adjacent to the carbamic acid group (that is,at the α,β-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH₂CH₂— group adjacent to the carbamic acid group (that is, at theα,β-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₄₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group, that adjacent alkylene group has a—CH═CH— group adjacent to the carbamic acid group (that is, at theα,β-position).

Examples of substituents on Q² include, but are not limited to, thosedescribed under the heading “Substituents” below.

In one embodiment, the optional substituents on Q² are as defined underthe heading “The Cyclyl Group, Cy: Optionally Substituted Phenyl:Substituents.”

The Acid Leader Group, Q²: Alkylene

In one embodiment, the acid leader group, Q², is C₄₋₈alkylene, and isoptionally substituted, and has a backbone length of at least 4 atoms.

In one embodiment, Q² is independently a saturated C₄₋₈alkylene group.

In one embodiment, Q² is independently a partially unsaturatedC₄₋₈alkylene group.

In one embodiment, Q² is independently an aliphatic C₄₋₈alkylene group

In one embodiment, Q² is independently a linear C₄₋₈alkylene group.

In one embodiment, Q² is independently a branched C₄₋₈alkylene group.

In one embodiment, Q² is independently an alicyclic C₄₋₈alkylene group.

In one embodiment, Q² is independently a saturated aliphaticC₄₋₈alkylene group.

In one embodiment, Q² is independently a saturated linear C₄₋₈alkylenegroup.

In one embodiment, Q² is independently a saturated branched C₄₋₈alkylenegroup.

In one embodiment, Q² is independently a saturated alicyclicC₄₋₈alkylene group.

In one embodiment, Q² is independently a partially unsaturated aliphaticC₄₋₈alkylene group.

In one embodiment, Q² is independently a partially unsaturated linearC₄₋₈alkylene group.

In one embodiment, Q² is independently a partially unsaturated branchedC₄₋₈alkylene group.

In one embodiment, Q² is independently a partially unsaturated alicyclicC₄₋₈alkylene group.

Note that, for embodiments excluding, e.g., certain backbone lengths,absence of adjacent carbon-carbon double bonds, etc., it is to beunderstood that the corresponding species listed below are similarlyexcluded from the respective embodiments discussed below.

In one embodiment, Q² is independently selected from:

-   -   —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)_(r), —(CH₂)₈—;    -   —CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—,    -   —CH₂CH₂CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₃)—, —CH(CH₃)CH₂CH₂CH₂CH(CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—,        —CH₂CH₂CH(CH₂CH₃)CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;    -   —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—,        —CH₂CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,        —CH₂CH₂CH₂CH═CHCH₂—, —CH₂CH₂CH₂CH₂CH═CH—;    -   —CH═CHCH═CH—;    -   —CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, —CH═CHCH₂CH═CH—;    -   —CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, —CH═CHCH₂CH₂CH═CH—,        —CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, —CH₂CH₂CH═CHCH═CH—;    -   —C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—,        —CH—CHCH═C(CH₃);    -   —C≡CCH₂CH₂—, —CH₂C≡CCH₂—, —CH₂CH₂C≡C—;    -   —C═CCH(CH₃)CH₂—, —C≡CCH₂CH(CH₃)—;    -   —CH(CH₃)C≡CCH₂—, —CH₂C≡CCH(CH₃)—;    -   —CH(CH₃)CH₂C≡C—, —CH₂CH(CH₃)C≡C—;    -   —C≡CCH═CH—, —CH═CHC≡C—, —C≡CC≡C—;    -   —C≡CCH₂CH₂CH₂—, —CH₂CH₂CH₂C≡C—;    -   —C≡CCH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂C≡C—;    -   —C≡CCH═CHCH═CH—, —CH═CHC≡C—CH═CH—, —CH═CHCH═CHC≡C—;    -   —C(CH₃)═CHC≡C—, —CH═C(CH₃)C≡C—, —C≡CC(CH₃)═CH—, —C≡CCH═C(CH₃)—;    -   cyclopentylene cyclopentenylene;    -   cyclohexylene, cyclohexenylene, cyclohexadienylene;

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—;    -   —(CH₂)₆—;    -   —(CH₂)₇—;    -   —(CH₂)₈—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—;    -   —CH₂CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH(CH₃)CH₂CH₂—;    -   —CH(CH₃)CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH₂CH═CH—;    -   —CH₂CH₂CH₂CH₂CH═CH—;

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—;    -   —(CH₂)₆—;    -   —(CH₂)₇—;    -   —(CH₂)₈—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—;    -   —CH₂CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH₂CH═CH—; and,    -   —CH₂CH₂CH₂CH₂CH═CH—.

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, and —(CH₂)₈—.        The Acid Leader Group, Q²: Arylene

In one embodiment, the acid leader group, Q², is independently:

-   -   C₅₋₂₀arylene (denoted —Ar—),    -   and is optionally substituted,    -   and has a backbone length of at least 4 atoms.

In one embodiment, Q² is C₅₋₂₀arylene; and is optionally substituted.

In one embodiment, Q² is C₅₋₆arylene; and is optionally substituted.

In one embodiment, Q² is phenylene; and is optionally substituted.

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

The Acid Leader Group, Q²:

Alkylene-Arylene, Arylene-Alkylene, and Alkylene-Arylene-Alkylene

In one preferred embodiment, the acid leader group, Q², isindependently:

-   -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene; or,    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one preferred embodiment, the acid leader group, Q², isindependently:

-   -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one preferred embodiment, the acid leader group, Q², isindependently:

-   -   C₁₋₇alkylene-C₅₋₂₀arylene; or,    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one preferred embodiment, the acid leader group, Q², isindependently:

-   -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one preferred embodiment, Q² is independently:

-   -   C₅₋₆arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₆arylene; or,    -   C₁₋₇alkylene-C₅₋₆arylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one preferred embodiment, Q² is independently:

-   -   phenylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-phenylene; or,    -   C₁₋₇alkylene-phenylene-C₁₋₇alkylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, Q² is C₁₋₇alkylene-C₅₋₂₀arylene; and is optionallysubstituted.

In one embodiment, Q² is C₁₋₇alkylene-C₅₋₆arylene; and is optionallysubstituted.

In one embodiment, Q² is independently C₁₋₇alkylene-phenylene; and isoptionally substituted.

In one embodiment, Q² is C₅₋₂₀arylene-C₁₋₇alkylene; and is optionallysubstituted.

In one embodiment, Q² is C₅₋₆arylene-C₁₋₇alkylene; and is optionallysubstituted.

In one embodiment, Q² is independently phenylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is independentlyC₁₋₇alkylene-phenylene-C₁₋₇alkylene; and is optionally substituted.

In the above arylene-alkylene (denoted —Ar—R^(Q22)—), alkylene-arylene(denoted —R^(Q21)—Ar—), and alkylene-arylene-alkylene (denoted—R^(Q21)—Ar—R^(Q22)) groups, each of R^(Q21) and R^(Q22) isindependently C₁₋₇alkylene.

In one embodiment, in the above arylene-alkylene, alkylene-arylene, andalkylene-arylene-alkylene groups, each alkylene group is independently:

(a) a saturated C₁₋₇alkylene group; or:

(b) a partially unsaturated C₂₋₇alkylene group; or:

(c) an aliphatic C₁₋₇alkylene group; or:

(d) a linear C₁₋₇alkylene group; or:

(e) a branched C₂₋₇alkylene group; or:

(f) a saturated aliphatic C₁₋₇alkylene group; or:

(g) a saturated linear C₁₋₇alkylene group; or

(h) a saturated branched C₂₋₇alkylene group; or

(i) a partially unsaturated aliphatic C₂₋₇alkylene group; or:

(j) a partially unsaturated linear C₂₋₇alkylene group; or:

(k) a partially unsaturated branched C₂₋₇alkylene group;

and is optionally substituted.

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

Alkylene Groups R^(Q21) and R^(Q22): Certain Embodiments

Note that, for embodiments excluding, e.g., certain backbone lengths,absence of adjacent carbon-carbon double bonds, etc., it is to beunderstood that the corresponding species listed below are similarlyexcluded from the respective embodiments discussed below.

In one embodiment, each of R^(Q21) and R^(Q22) is independently asdefined for Q¹ under the heading “The Cyclyl Leader Group, Q¹: Alkylene:Certain Embodiments.”

In one embodiment, R^(Q21) is independently selected from:

-   -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,    -   —CH₂—CH═CH—; and,    -   —CH₂—CH═CH—CH═CH—.

In one embodiment, R^(Q21) is independently selected from:

-   -   —CH₂—, —CH₂CH₂—, and —CH₂—CH═CH—.

In one embodiment, R^(Q21) is independently selected from:

-   -   —CH₂— and, —CH₂CH₂—.

In one embodiment, R^(Q21) is independently —CH₂—.

In one embodiment, R^(Q21) is independently —CH₂CH₂—.

In one embodiment, R^(Q21) is independently —CH₂—CH═CH—.

In one embodiment, R^(Q21) is independently cis —CH₂—CH═CH—.

In one embodiment, R^(Q21) is independently trans —CH₂—CH═CH—.

In one embodiment, R^(Q22) is independently selected from:

-   -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—;    -   —CH═CH—;    -   —CH₂—CH═CH—;    -   —CH═CH—CH═CH—; and,    -   —CH₂—CH═CH—CH═CH—.

In one embodiment, R^(Q22) is independently selected from:

-   -   —CH₂—, —CH₂CH₂—, —CH═CH—, and —CH₂—CH═CH—.

In one embodiment, R^(Q22) is independently selected from:

-   -   —CH₂—, —CH₂CH₂—, and —CH═CH—.        The Acid Leader Group, Q² Certain Phenylene-Containing        Embodiments

In one embodiment, Q² is independently:

-   -   phenylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, Q² is independently:

-   -   methylene-phenylene;    -   ethylene-phenylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, Q² is independently:

-   -   phenylene-methylene;    -   phenylene-ethylene; or,    -   phenylene-ethenylene (also known as phenylene-vinylene);    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In one embodiment, Q² is independently:

-   -   methylene-phenylene-methylene;    -   methylene-phenylene-ethylene;    -   methylene-phenylene-ethenylene;    -   ethylene-phenylene-methylene;    -   ethylene-phenylene-ethylene;    -   ethylene-phenylene-ethenylene;    -   and is optionally substituted;    -   and has a backbone length of at least 4 atoms.

In the above phenylene, phenylene-alkylene, alkylene-phenylene, andalkylene-phenylene-alkylene groups, the phenylene linkage may be ortho(i.e., 1,2-), meta (i.e., 1,3-), or para (i.e., 1,4-), and the phenylenegroup is optionally substituted with from 1 to 4 substituents, R^(B):

In one embodiment, the phenylene linkage is meta or para.

In one embodiment, the phenylene linkage is meta.

In one embodiment, the phenylene linkage is para.

In one embodiment, m is an integer from 0 to 4.

In one embodiment, m is an integer from 0 to 3.

In one embodiment, m is an integer from 0 to 2.

In one embodiment, m is 0 or 1.

In one embodiment, m is an integer from 1 to 4.

In one embodiment, m is an integer from 1 to 3.

In one embodiment, m is 1 or 2.

In one embodiment, m is 4.

In one embodiment, m is 3.

In one embodiment, m is 2.

In one embodiment, m is 1.

In one embodiment, m is 0.

In one embodiment, the phenylene group is unsubstituted.

In one embodiment, the phenylene group is optionally substituted.

In one embodiment, the phenylene group is substituted.

Examples of substituents, R^(B), include, but are not limited to, thosedescribed under the heading “Substituents” below.

In one embodiment, the substituents, R^(B), are as defined under theheading “The Cyclyl Group, Cy: Optionally Substituted Phenyl:Substituents.”

Examples of preferred substituents, R^(B), include, but are not limitedto, the following: fluoro, chloro, methyl, ethyl, isopropyl, t-butyl,trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio,amino, dimethylamino, diethylamino, morpholino, acetamido, nitro, andphenyl.

In one embodiment, the compounds have the following formula, in which Q²is para-arylene:

In one embodiment, the compounds have the following formula, in which Q²is alkylene-meta/para-arylene:

In one embodiment, the compounds have the following formula, in which Q²is arylene-meta/para-alkylene:

In one embodiment, the compounds have the following formula, in which Q²is alkylene-arylene-meta/para-alkylene:

In one embodiment, Q² has the following formula (referred to herein as“para-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-meta/para-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-meta-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted methylene-meta-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-meta/para-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-meta-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted ethylene-meta-phenylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta/para-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta/para-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted methylene-phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta/para-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted ethylene-phenylene-meta-methylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta/para-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted phenylene-meta/para-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta/para-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“phenylene-meta-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted phenylene-meta-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta/para-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted methylene-phenylene-meta/para-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted methylene-phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta/para-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“methylene-phenylene-meta-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted methylene-phenylene-meta-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta/para-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted ethylene-phenylene-meta-trans-ethenylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta/para-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“ethylene-phenylene-meta-ethylene”):

In one embodiment, Q² has the following formula (referred to herein as“unsubstituted ethylene-phenylene-meta-ethylene”):

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

Examples of Specific Embodiments

Some individual embodiments of the present invention include thefollowing compounds.

1.

PX117402 (Ex 140) 2.

PX117403 (Ex 141) 3.

PX117404 (Ex 142) 4.

PX117764 (Ex 143) 5.

PX117768 (Ex 144) 6.

PX118490 (Ex 40) 7.

PX118491 (Ex 41) 8.

PX118791 (Ex 145) 9.

PX118792 (Ex 146) 10.

PX118793 (Ex 147) 11.

PX118794 (Ex 148) 12.

PX118807 (Ex 45) 13.

PX118810 (Ex 42) 14.

PX118811 (Ex 43) 15.

PX118812 (Ex 44) 16.

PX118830 (Ex 149) 17.

PX118831 (Ex 150) 18.

PX118832 (Ex 151) 19.

PX118844 (Ex 163) 20.

PX118845 (Ex 164) 21.

PX118846 (Ex 152) 22.

PX118847 (Ex 153) 23.

PX118848 (Ex 165) 24.

PX118849 (Ex 154) 25.

PX118850 (Ex 166) 26.

PX118859 (Ex 174) 27.

PX118860 (Ex 175) 28.

PX118870 (Ex 52) 29.

PX118871 (Ex 53) 30.

PX118872 (Ex 54) 31.

PX118873 (Ex 55) 32.

PX118874 (Ex 56) 33.

PX118875 (Ex 57) 34.

PX118876 (Ex 58) 35.

PX118877 (Ex 59) 36.

PX118878 (Ex 60) 37.

PX118882 (Ex 72) 38.

PX118891 (Ex 74) 39.

PX118892 (Ex 75) 40.

PX118893 (Ex 61) 41.

PX118894 (Ex 62) 42.

PX118898 (Ex 176) 43.

PX118899 (Ex 177) 44.

PX118900 (Ex 178) 45.

PX118901 (Ex 179) 46.

PX118902 (Ex 180) 47.

PX118903 (Ex 181) 48.

PX118904 (Ex 182) 49.

PX118905 (Ex 76) 50.

PX118906 (Ex 77) 51.

PX118907 (Ex 78) 52.

PX118908 (Ex 183) 53.

PX118909 (Ex 184) 54.

PX118910 (Ex 79) 55.

PX118911 (Ex 80) 56.

PX118913 (Ex 63) 57.

PX118914 (Ex 64) 58.

PX118918 (Ex 73) 59.

PX118927 (Ex 155) 60.

PX118928 (Ex 167) 61.

PX118929 (Ex 168) 62.

PX118930 (Ex 156) 63.

PX118931 (Ex 157) 64.

PX118932 (Ex 158) 65.

PX118933 (Ex 46) 66.

PX118934 (Ex 48) 67.

PX118935 (Ex 49) 68.

PX118937 (Ex 70) 69.

PX118951 (Ex 47) 70.

PX118965 (Ex 71) 71.

PX118967 (Ex 159) 72.

PX118968 (Ex 169) 73.

PX118969 (Ex 170) 74.

PX118970 (Ex 171) 75.

PX118971 (Ex 50) 76.

PX118972 (Ex 51) 77.

PX118978 (Ex 172) 78.

PX118989 (Ex 160) 79.

PX118990 (Ex 161) 80.

PX118991 (Ex 162) 81.

PX118994 (Ex 173) 82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

Note that, where the above examples are salts (e.g., PX118932,PX118882), other analogous salts may also be prepared.

Chemical Terms

The term “carbo,” “carbyl,” “hydrocarbon” and “hydrocarbyl,” as usedherein, pertain to compounds and/or groups which have only carbon andhydrogen atoms (but see “carbocyclic” below).

The term “hetero,” as used herein, pertains to compounds and/or groupswhich have at least one heteroatom, for example, multivalent heteroatoms(which are also suitable as ring heteroatoms) such as boron, silicon,nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonlynitrogen, oxygen, and sulfur) and monovalent heteroatoms, such asfluorine, chlorine, bromine, and iodine.

The term “saturated,” as used herein, pertains to compounds and/orgroups which do not have any carbon-carbon double bonds or carbon-carbontriple bonds.

The term “unsaturated,” as used herein, pertains to compounds and/orgroups which have at least one carbon-carbon double bond orcarbon-carbon triple bond.

The term “aliphatic,” as used herein, pertains to compounds and/orgroups which are linear or branched, but not cyclic (also known as“acyclic” or “open-chain” groups).

The term “ring,” as used herein, pertains to a closed ring of from 3 to10 covalently linked atoms, more preferably 3 to 8 covalently linkedatoms, yet more preferably 5 to 6 covalently linked atoms. A ring may bean alicyclic ring or an aromatic ring. The term “alicyclic ring,” asused herein, pertains to a ring which is not an aromatic ring.

The term “carbocyclic ring,” as used herein, pertains to a ring whereinall of the ring atoms are carbon atoms.

The term “carboaromatic ring,” as used herein, pertains to an aromaticring wherein all of the ring atoms are carbon atoms.

The term “heterocyclic ring,” as used herein, pertains to a ring whereinat least one of the ring atoms is a multivalent ring heteroatom, forexample, nitrogen, phosphorus, silicon, oxygen, or sulfur, though morecommonly nitrogen, oxygen, or sulfur. Preferably, the heterocyclic ringhas from 1 to 4 heteroatoms.

The term “cyclic compound,” as used herein, pertains to a compound whichhas at least one ring. The term “cyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a cyclic compound.

Where a cyclic compound has two or more rings, they may be fused (e.g.,as in naphthalene), bridged (e.g., as in norbornane), spiro (e.g., as inspiro[3.3]heptane), or a combination thereof. Cyclic compounds with onering may be referred to as “monocyclic” or “mononuclear,” whereas cycliccompounds with two or more rings may be referred to as “polycyclic” or“polynuclear.”

The term “carbocyclic compound,” as used herein, pertains to a cycliccompound which has only carbocyclic ring(s).

The term “heterocyclic compound,” as used herein, pertains to a cycliccompound which has at least one heterocyclic ring.

The term “aromatic compound,” as used herein, pertains to a cycliccompound which has at least one aromatic ring.

The term “carboaromatic compound,” as used herein, pertains to a cycliccompound which has only carboaromatic ring(s).

The term “heteroaromatic compound,” as used herein, pertains to a cycliccompound which has at least one heteroaromatic ring.

The term “monodentate substituents,” as used herein, pertains tosubstituents which have one point of covalent attachment.

The term “monovalent monodentate substituents,” as used herein, pertainsto substituents which have one point of covalent attachment, via asingle bond. Examples of such substituents include halo, hydroxy, andalkyl.

The term “multivalent monodentate substituents,” as used herein,pertains to substituents which have one point of covalent attachment,but through a double bond or triple bond. Examples of such substituentsinclude oxo, imino, alkylidene, and alklidyne.

The term “bidentate substituents,” as used herein, pertains tosubstituents which have two points of covalent attachment, and which actas a linking group between two other moieties. Examples of suchsubstituents include alkylene and arylene.

Substituents

The phrase “optionally substituted,” as used herein, pertains to aparent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted,” as used herein,pertains to a parent group which bears one or more substituents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, appended to, or ifappropriate, fused to, a parent group. A wide variety of substituentsare well known, and methods for their formation and introduction into avariety of parent groups are also well known.

The substituents are described in more detail below.

Alkyl: The term “alkyl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 20 carbon atoms (unless otherwise specified),which may be aliphatic or alicyclic, and which may be saturated,partially unsaturated, or fully unsaturated. Thus, the term “alkyl”includes the subclasses alkenyl, alkynyl, cycloalkyl, etc., discussedbelow.

In this context, the prefixes (e.g., C₁₋₄, C₁₋₇, C₁₋₂₀, C₂₋₇, C₃₋₇,etc.) denote the number of carbon atoms, or range of number of carbonatoms. For example, the term “C₁₋₄alkyl,” as used herein, pertains to analkyl group having from 1 to 4 carbon atoms. Examples of groups of alkylgroups include C₁₋₄alkyl (“lower alkyl”), C₁₋₇alkyl, and C₁₋₂₀alkyl.

Examples of (unsubstituted) saturated alkyl groups include, but are notlimited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl(C₅), hexyl (C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀),undecyl (C₁₁), dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄),pentadecyl (C₁₅), and eicodecyl (C₂₀).

Examples of (unsubstituted) saturated linear alkyl groups include, butare not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl(C₄), n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of (unsubstituted) saturated branched alkyl groups includeiso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),iso-pentyl (C₅), and neo-pentyl (C₅).

Cycloalkyl: The term “cycloalkyl,” as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 20ring atoms (unless otherwise specified). Preferably, each ring has from3 to 7 ring atoms.

Examples of (unsubstituted) saturated cylcoalkyl groups include, but arenot limited to, those derived from: cyclopropane (C₃), cyclobutane (C₄),cyclopentane (C₅), cyclohexane (C₆), cycloheptane (C₇), norbornane (C₇),norpinane (C₇), norcarane (C₇), adamantane (C₁₀), and decalin(decahydronaphthalene) (C₁₀).

Examples of (substituted) saturated cycloalkyl groups, which are alsoreferred to herein as “alkyl-cycloalkyl” groups, include, but are notlimited to, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl,dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl,methylcyclohexyl, and dimethylcyclohexyl, menthane, thujane, carane,pinane, bornane, norcarane, and camphene.

Examples of (substituted) unsaturated cyclic alkenyl groups, which arealso referred to herein as “alkyl-cycloalkenyl” groups, include, but arenot limited to, methylcyclopropenyl, dimethylcyclopropenyl,methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl,dimethylcyclopentenyl, methylcyclohexenyl, and dimethylcyclohexenyl.

Examples of (substituted) cycloalkyl groups, with one or more otherrings fused to the parent cycloalkyl group, include, but are not limitedto, those derived from: indene (C₉), indan (e.g., 2,3-dihydro-1H-indene)(C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀), acenaphthene(C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene (C₁₅),aceanthrene (C₁₆). For example, 2H-inden-2-yl is a C₅cycloalkyl groupwith a substituent (phenyl) fused thereto.

Alkenyl: The term “alkenyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of groups ofalkenyl groups include C₂₋₄alkenyl, C₂₋₇alkenyl, C₂₋₂₀alkenyl.

Examples of (unsubstituted) unsaturated alkenyl groups include, but arenot limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃),2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (—C(CH₃)═CH₂), butenyl (C₄),pentenyl (C₅), and hexenyl (C₈).

Examples of (unsubstituted) unsaturated cyclic alkenyl groups, which arealso referred to herein as “cycloalkenyl” groups, include, but are notlimited to, cyclopropenyl (C₃), cyclobutenyl (C₄), cyclopentenyl (C₅),and cyclohexenyl (C₆).

Alkynyl: The term “alkynyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄alkynyl, C₂₋₇alkynyl, C₂₋₂₀alkynyl.

Examples of (unsubstituted) unsaturated alkynyl groups include, but arenot limited to, ethynyl (ethinyl, —C≡CH) and 2-propynyl (propargyl,—CH₂—C≡CH).

Alkylidene: The term “alkylidene,” as used herein, pertains to adivalent monodentate moiety obtained by removing two hydrogen atoms froma carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms(unless otherwise specified), which may be aliphatic or alicyclic, or acombination thereof, and which may be saturated, partially unsaturated,or fully unsaturated. Examples of groups of alkylidene groups includeC₁₋₄alkylidene, C₁₋₇alkylidene, C₁₋₂₀alkylidene.

Examples of alkylidene groups include, but are not limited to,methylidene (═CH₂), ethylidene (═CH—CH₃), vinylidene (═C═CH₂), andisopropylidene (═C(CH₃)₂). An example of a substituted alkylidene isbenzylidene (═CH-Ph).

Alkylidyne: The term “alkylidyne,” as used herein, pertains to atrivalent monodentate moiety obtained by removing three hydrogen atomsfrom a carbon atom of a hydrocarbon compound having from 1 to 20 carbonatoms (unless otherwise specified), which may be aliphatic or alicyclic,or a combination thereof, and which may be saturated, partiallyunsaturated, or fully unsaturated. Examples of groups of alkylidynegroups include C₁₋₄alkylidyne, C₁₋₇alkylidyne, C₁₋₂₀alkylidyne.

Examples of alkylidyne groups include, but are not limited to,methylidyne (≡CH) and ethylidyne (≡C—CH₃).

Carbocyclyl: The term “carbocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a carbocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified). Preferably, each ring has from 3 to 7 ringatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms. For example, theterm “C₅₋₆carbocyclyl,” as used herein, pertains to a carbocyclyl grouphaving 5 or 6 ring atoms. Examples of groups of carbocyclyl groupsinclude C₃₋₂₀carbocyclyl, C₃₋₁₀carbocyclyl, C₅₋₁₀carbocyclyl,C₃₋₇carbocyclyl, and C₅₋₇carbocyclyl.

Examples of carbocyclic groups include, but are not limited to, thosedescribed above as cycloalkyl groups; and those described below ascarboaryl groups.

Heterocyclyl: The term “heterocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a heterocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified), of which from 1 to 10 are ringheteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of whichfrom 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl,” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀heterocyclyl,C₃₋₇heterocyclyl, C₅₋₇heterocyclyl, and C₅₋₆heterocyclyl.

Examples of (non-aromatic) monocyclic heterocyclyl groups include, butare not limited to, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrroleor 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆),dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole(dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆),pyran (C₆), oxepin (C₇);S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅),thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);O₃: trioxane (C₆);N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline(C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole(C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆),dihydrooxazine (C₆), oxazine (C₆);N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);N₂O₁: oxadiazine (C₆);O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,N₁O₁S₁: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groupsinclude saccharides, in cyclic form, for example, furanoses (C₅), suchas arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, andpyranoses (C₆), such as allopyranose, altropyranose, glucopyranose,mannopyranose, gulopyranose, idopyranose, galactopyranose, andtalopyranose.

Examples of heterocyclyl groups which are also heteroaryl groups aredescribed below with aryl groups.

Aryl: The term “aryl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from an aromatic ring atom of anaromatic compound, which moiety has from 3 to 20 ring atoms (unlessotherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g., C₃₋₂₀ C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆aryl,” as used herein,pertains to an aryl group having 5 or 6 ring atoms. Examples of groupsof aryl groups include C₃₋₂₀aryl, C₃₋₁₂aryl, C₅₋₁₂aryl, C₅₋₇aryl, andC₅₋₆aryl.

The ring atoms may be all carbon atoms, as in “carboaryl groups” (e.g.,C₅₋₂₀carboaryl).

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e., phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indene (C₉), isoindene (C₉), and fluorene (C₁₃).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups” (e.g., C₅₋₂₀heteroaryl).

Examples of monocyclic heteroaryl groups include, but are not limitedto, those derived from:

N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);

O₁: furan (oxole) (C₅);

S₁: thiophene (thiole) (C₅);

N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);

N₂O₁: oxadiazole (furazan) (C₅);

N₃O₁: oxatriazole (C₅);

N₁S₁: thiazole (C₅), isothiazole (C₅);

N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g.,cytosine, thymine, uracil), pyrazine (1,4-diazine) (C₆);

N₃: triazole (C₅), triazine (C₆); and,

N₄: tetrazole (C₅).

Examples of heterocyclic groups (some of which are also heteroarylgroups) which comprise fused rings, include, but are not limited to:

-   -   C₉heterocyclic groups (with 2 fused rings) derived from        benzofuran (O₁), isobenzofuran (O₁), indole (N₁), isoindole        (N₁), indolizine (N₁), indoline (N₁), isoindoline (N₁), purine        (N₄) (e.g., adenine, guanine), benzimidazole (N₂), indazole        (N₂), benzoxazole (N₁O₁), benzisoxazole (N₁O₁), benzodioxole        (O₂), benzofurazan (N₂O₁), benzotriazole (N₃), benzothiofuran        (S₁), benzothiazole (N₁S₁), benzothiadiazole (N₂S);    -   C₁₀heterocyclic groups (with 2 fused rings) derived from        chromene (O₁), isochromene (O₁), chroman (O₁), isochroman (O₁),        benzodioxan (O₂), quinoline (N₁), isoquinoline (N₁), quinolizine        (N₁), benzoxazine (N₁O₁), benzodiazine (N₂), pyridopyridine        (N₂), quinoxaline (N₂), quinazoline (N₂), cinnoline (N₂),        phthalazine (N₂), naphthyridine (N₂), pteridine (N₄);    -   C₁₃heterocyclic groups (with 3 fused rings) derived from        carbazole (N₁), dibenzofuran (O₁), dibenzothiophene (S₁),        carboline (N₂), perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄heterocyclic groups (with 3 fused rings) derived from        acridine (N₁), xanthene (O₁), thioxanthene (S₁), oxanthrene        (O₂), phenoxathiin (O₁S₁), phenazine (N₂), phenoxazine (N₁O₁),        phenothiazine (N₁S₁), thianthrene (S₂), phenanthridine (N₁),        phenanthroline (N₂), phenazine (N₂).

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —NH— group may be N-substituted, that is, as—NR—. For example, pyrrole may be N-methyl substituted, to giveN-methypyrrole. Examples of N-substituents include, but are not limitedto C₁₋₇alkyl, C₃₋₂₀heterocyclyl, C₅₋₂₀aryl, and acyl groups.

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —N═ group may be substituted in the form ofan N-oxide, that is, as —N(→O)═ (also denoted —N⁺(→O⁻)═). For example,quinoline may be substituted to give quinoline N-oxide; pyridine to givepyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also knownas benzofuroxan).

Cyclic groups may additionally bear one or more oxo (═O) groups on ringcarbon atoms.

Monocyclic examples of such groups include, but are not limited to,those derived from:

C₅: cyclopentanone, cyclopentenone, cyclopentadienone;

C₆: cyclohexanone, cyclohexenone, cyclohexadienone;

O₁: furanone (C₅), pyrone (C₆);

N₁: pyrrolidone (pyrrolidinone) (C₅), piperidinone (piperidone) (C₆),piperidinedione (C₆);

N₂: imidazolidone (imidazolidinone) (C₅), pyrazolone (pyrazolinone)(C₅), piperazinone (C₆), piperazinedione (C₆), pyridazinone (C₆),pyrimidinone (C₆) (e.g., cytosine), pyrimidinedione (C₆) (e.g., thymine,uracil), barbituric acid (C₆);

N₁S₁: thiazolone (C₅), isothiazolone (C₅);

N₁O₁: oxazolinone (C₅).

Polycyclic examples of such groups include, but are not limited to,those derived from:

C₉: indenedione;

C₁₀: tetralone, decalone;

C₁₄: anthrone, phenanthrone;

N₁: oxindole (C₉);

O₁: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C₁₀);

N₁O₁: benzoxazolinone (C₉), benzoxazolinone (C₁₀);

N₂: quinazolinedione (C₁₀);

N₄: purinone (C₉) (e.g., guanine).

Still more examples of cyclic groups which bear one or more oxo (═O)groups on ring carbon atoms include, but are not limited to, thosederived from:

-   -   cyclic anhydrides (—C(═O)—O—C(═O)— in a ring), including but not        limited to maleic anhydride (C₅), succinic anhydride (C₅), and        glutaric anhydride (C₆);    -   cyclic carbonates (—O—C(═O)—O— in a ring), such as ethylene        carbonate (C₅) and 1,2-propylene carbonate (C₅);    -   imides (—C(═O)—NR—C(═O)— in a ring), including but not limited        to, succinimide (C₅), maleimide (C₅), phthalimide, and        glutarimide (C₆);    -   lactones (cyclic esters, —O—C(═O)— in a ring), including, but        not limited to, β-propiolactone, γ-butyrolactone,        δ-valerolactone (2-piperidone), and ε-caprolactone;    -   lactams (cyclic amides, —NR—C(═O)— in a ring), including, but        not limited to, β-propiolactam (C₄), γ-butyrolactam        (2-pyrrolidone) (C₅), δ-valerolactam (C₆), and ε-caprolactam        (C₇);    -   cyclic carbamates (—O—C(═O)—NR— in a ring), such as        2-oxazolidone (C₅);    -   cyclic ureas (—NR—C(═O)—NR— in a ring), such as 2-imidazolidone        (C₅) and pyrimidine-2,4-dione (e.g., thymine, uracil) (C₆).

The above alkyl, alkylidene, alkylidyne, heterocyclyl, and aryl groups,whether alone or part of another substituent, may themselves optionallybe substituted with one or more groups selected from themselves and theadditional substituents listed below.

Hydrogen: —H. Note that if the substituent at a particular position ishydrogen, it may be convenient to refer to the compound as being“unsubstituted” at that position.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇alkylgroup (also referred to as a C₁₋₇alkoxy group, discussed below), aC₃₋₂₀heterocyclyl group (also referred to as a C₃₋₂₀heterocyclyloxygroup), or a C₅₋₂₀aryl group (also referred to as a C₅₋₂₀aryloxy group),preferably a C₁₋₇alkyl group.

C₁₋₇alkoxy: —OR, wherein R is a C₁₋₇alkyl group. Examples of C₁₋₇alkoxygroups include, but are not limited to, —OMe (methoxy), —OEt (ethoxy),—O(nPr) (n-propoxy), —O(iPr) (isopropoxy), —O(nBu) (n-butoxy), —O(sBu)(sec-butoxy), —O(iBu) (isobutoxy), and —O(tBu) (tert-butoxy).

Acetal: —CH(OR¹)(OR²), wherein R¹ and R² are independently acetalsubstituents, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group, or, in the case of a“cyclic” acetal group, R¹ and R², taken together with the two oxygenatoms to which they are attached, and the carbon atoms to which they areattached, form a heterocyclic ring having from 4 to 8 ring atoms.Examples of acetal groups include, but are not limited to, —CH(OMe)₂,—CH(OEt)₂, and —CH(OMe)(OEt).

Hemiacetal: —CH(OH)(OR¹), wherein R¹ is a hemiacetal substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of hemiacetal groupsinclude, but are not limited to, —CH(OH)(OMe) and —CH(OH)(OEt).

Ketal: —CR(OR¹)(OR²), where R¹ and R² are as defined for acetals, and Ris a ketal substituent other than hydrogen, for example, a C₁₋₇alkylgroup, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably aC₁₋₇alkyl group. Examples ketal groups include, but are not limited to,—C(Me)(OMe)₂, —C(Me)(OEt)₂, —C(Me)(OMe)(OEt), —C(Et)(OMe)₂,—C(Et)(OEt)₂, and —C(Et)(OMe)(OEt).

Hemiketal: —CR(OH)(OR¹), where R¹ is as defined for hemiacetals, and Ris a hemiketal substituent other than hydrogen, for example, a C₁₋₇alkylgroup, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably aC₁₋₇alkyl group. Examples of hemiacetal groups include, but are notlimited to, —C(Me)(OH)(OMe), —C(Et)(OH)(OMe), —C(Me)(OH)(OEt), and—C(Et)(OH)(OEt).

Oxo (keto, -one): ═O.

Thione (thioketone): ═S.

Imino (imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably hydrogen or a C₁₋₇alkyl group. Examples of estergroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇alkyl group (also referred to as C₁₋₇alkylacyl or C₁₋₇alkanoyl), aC₃₋₂₀heterocyclyl group (also referred to as C₃₋₂₀heterocyclylacyl), ora C₅₋₂₀aryl group (also referred to as C₅₋₂₀arylacyl), preferably aC₁₋₇alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph (benzoyl, phenone).

Acylhalide (haloformyl, halocarbonyl): —C(═O)X, wherein X is —F, —Cl,—Br, or —I, preferably —Cl, —Br, or —I.

Carboxy (carboxylic acid): —C(═O)OH.

Thiocarboxy (thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy (thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy (thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of acyloxygroups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Oxycarboyloxy: —OC(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of ester groups include,but are not limited to, —OC(═O)OCH₃, —OC(═O)OCH₂CH₃, —OC(═O)OC(CH₃)₃,and —OC(═O)OPh.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group, and R² isan acyl substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclylgroup, or a C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group.Examples of acylamide groups include, but are not limited to,—NHC(—O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may together forma cyclic structure, as in, for example, succinimidyl, maleimidyl, andphthalimidyl:

Aminocarbonyloxy: —OC(═O)NR¹R², wherein R¹ and R² are independentlyamino substituents, as defined for amino groups. Examples ofaminocarbonyloxy groups include, but are not limited to, —OC(═O)NH₂,—OC(═O)NHMe, —OC(═O)NMe₂, and —OC(═O)NEt₂.

Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof amido groups include, but are not limited to, —C(═S)NH₂,—C(═S)NHCH₃″—C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen or aC₁₋₇alkyl group. Examples of ureido groups include, but are not limitedto, —NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂,

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇alkyl group (also referred to asC₁₋₇alkylamino or di-C₁₋₇alkylamino), a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group, or, in the case of a“cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), ortertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃,—NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic aminogroups include, but are not limited to, aziridino, azetidino,pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Imino: ═NR, wherein R is an imino substituent, for example, for example,hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably H or a C₁₋₇alkyl group. Examples of imino groupsinclude, but are not limited to, ═NH, ═NMe, and ═NEt.

Amidine (amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Cyano(nitrile, carbonitrile): —CN.

Isocyano: —NC.

Cyanato: —OCN.

Isocyanato: —NCO.

Isothiocyano(isothiocyanato): —NCS.

Sulfhydryl (thiol, mercapto): —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇alkyl group (also referred to as a C₁₋₇alkylthio group),a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of C₁₋₇alkylthio groups include, but are not limited to,—SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group (also referred to herein as C₁₋₇alkyldisulfide). Examples of C₁₋₇alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of sulfinegroups include, but are not limited to, —S(═O)CH₃ and —S(═O)CH₂CH₃.

Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇alkyl group, a C₅₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl,mesyl), —S(═O)₂CF₃ (triflyl), —S(═O)₂CH₂CH₃ (esyl), —S(═O)₂C₄F₉(nonaflyl), —S(═O)₂CH₂CF₃ (tresyl), —S(═O)₂CH₂CH₂NH₂ (tauryl), —S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl),4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl),4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

Sulfinic acid (sulfino): —S(═O)OH, —SO₂H.

Sulfonic acid (sulfo): —S(═O)₂OH, —SO₃H.

Sulfinate (sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfinate groups include, but are not limited to, —S(═O)OCH₃(methoxysulfinyl; methyl sulfinate) and —S(═O)OCH₂CH₃ (ethoxysulfinyl;ethyl sulfinate).

Sulfonate (sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfonate groups include, but are not limited to, —S(═O)₂OCH₃(methoxysulfonyl; methyl sulfonate) and —S(═O)₂OCH₂CH₃ (ethoxysulfonyl;ethyl sulfonate).

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃ (mesylate) and—OS(═O)₂CH₂CH₃ (esylate).

Sulfate: —OS(═O)₂OR; wherein R is a sulfate substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfate groups include, butare not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.

Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): —S(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of sulfamyl groups include, but are not limitedto, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃),—S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

In many cases, substituents may themselves be substituted. For example,a C₁₋₇alkyl group may be substituted with, for example, hydroxy (alsoreferred to as a C₁₋₇hydroxyalkyl group), C₁₋₇alkoxy (also referred toas a C₁₋₇alkoxyalkyl group), amino (also referred to as a C₁₋₇aminoalkylgroup), halo (also referred to as a C₁₋₇haloalkyl group), carboxy (alsoreferred to as a C₁₋₇carboxyalkyl group), and C₅₋₂₀aryl (also referredto as a C₅₋₂₀aryl-C₁₋₇alkyl group).

Similarly, a C₅₋₂₀aryl group may be substituted with, for example,hydroxy (also referred to as a C₅₋₂₀hydroxyaryl group), halo (alsoreferred to as a C₅₋₂₀haloaryl group), amino (also referred to as aC₅₋₂₀aminoaryl group, e.g., as in aniline), C₁₋₇alkyl (also referred toas a C₁₋₇alkyl-C₅₋₂₀aryl group, e.g., as in toluene), and C₁₋₇alkoxy(also referred to as a C₁₋₇alkoxy-C₅₋₂₀aryl group, e.g., as in anisole).

These and other specific examples of such substituted-substituents aredescribed below.

C₁₋₇haloalkyl group: The term “C₁₋₇haloalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). Ifmore than one hydrogen atom has been replaced with a halogen atom, thehalogen atoms may independently be the same or different. Every hydrogenatom may be replaced with a halogen atom, in which case the group mayconveniently be referred to as a C₁₋₇ perhaloalkyl group.” Examples ofC₁₋₇haloalkyl groups include, but are not limited to, —CF₃, —CHF₂,—CH₂F, —CCl₃, —CBr₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃.

C₁₋₇haloalkoxy: —OR, wherein R is a C₁₋₇haloalkyl group. Examples ofC₁₋₇haloalkoxy groups include, but are not limited to, —OCF₃, —OCHF₂,—OCH₂F, —OCCl₃, —OCBr₃, —OCH₂CH₂F, —OCH₂CHF₂, and —OCH₂CF₃.

C₁₋₇hydroxyalkyl: The term “C₁₋₇hydroxyalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with a hydroxy group. Examples of C₁₋₇hydroxyalkyl groupsinclude, but are not limited to, —CH₂OH, —CH₂CH₂OH, and —CH(OH)CH₂OH.

C₁₋₇carboxyalkyl: The term “C₁₋₇carboxyalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with a carboxy group. Examples of C₁₋₇carboxyalkyl groupsinclude, but are not limited to, —CH₂COOH and —CH₂CH₂COOH.

C₁₋₇aminoalkyl: The term “C₁₋₇aminoalkyl group,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom hasbeen replaced with an amino group. Examples of C₁₋₇aminoalkyl groupsinclude, but are not limited to, —CH₂NH₂, —CH₂CH₂NH₂, and—CH₂CH₂N(CH₃)₂.

C₁₋₇aminoalkylamino: The term “C₁₋₇aminoalkylamino,” as used herein,pertains to an amino group, —NR¹R², in which one of the substituents, R¹or R², is itself a C₁₋₇aminoalkyl group (—C₁₋₇alkyl-NR¹R²). TheC₁₋₇aminoalkylamino may be represented, for example, by the formula—NR¹—C₁₋₇alkyl-NR¹R². Examples of amino-C₁₋₇alkylamino groups include,but are not limited to, groups of the formula —NR¹(CH₂)_(n)NR¹R², wheren is 1 to 6, for example, —NHCH₂NH₂, —NH(CH₂)₂NH₂, —NH(CH₂)₃NH₂,—NH(CH₂)₄NH₂, —NH(CH₂)₅NH₂, —NH(CH₂)₆NH₂, —NHCH₂NH(Me), —NH(CH₂)₂NH(Me),—NH(CH₂)₃NH(Me), —NH(CH₂)₄NH(Me), —NH(CH₂)₅NH(Me), —NH(CH₂)₆NH(Me),—NHCH₂NH(Et), —NH(CH₂)₂NH(Et), —NH(CH₂)₃NH(Et), —NH(CH₂)₄NH(Et),—NH(CH₂)₅NH(Et), and —NH(CH₂)₆NH(Et).

C₁₋₇alkyl-C₅₋₂₀aryl: The term “C₁₋₇alkyl-C₅₋₂₀aryl,” as used herein,describes certain C₅₋₂₀aryl groups which have been substituted with aC₁₋₇alkyl group. Examples of such groups include, but are not limitedto, tolyl (from toluene), xylyl (from xylene), mesityl (frommesitylene), and cumenyl (or cumyl, from cumene), and duryl (fromdurene).

C₁₋₇alkyl-C₅₋₂₀aryloxy: The term “C₁₋₇alkyl-C₅₋₂₀aryloxy,” as usedherein, describes certain C₅₋₂₀aryloxy groups which have beensubstituted with a C₁₋₇alkyl group. Examples of such groups include, butare not limited to, tolyloxy, xylyloxy, mesityloxy, cumenyloxy, andduryloxy.

C₅₋₂₀aryl-C₁₋₇alkyl: The term “C₅₋₂₀aryl-C₁₋₇alkyl,” as used herein,describers certain C₁₋₇alkyl groups which have been substituted with aC₅₋₂₀aryl group. Examples of such groups include, but are not limitedto, benzyl (phenylmethyl, PhCH₂—), benzhydryl (Ph₂CH—), trityl(triphenylmethyl, Ph₃C—), phenethyl (phenylethyl, Ph-CH₂CH₂—), styryl(Ph-CH═CH—), cinnamyl (Ph-CH═CH—CH₂—).

C₅₋₂₀aryl-C₁₋₇alkoxy: The term “C₅₋₂₀aryl-C₁₋₇alkoxy,” as used herein,describes certain C₁₋₇alkoxy groups which have been substituted with aC₅₋₂₀aryl group. Examples of such groups include, but are not limitedto, benzyloxy, benzhydryloxy, trityloxy, phenethoxy, styryloxy, andcimmamyloxy.

C₅₋₂₀haloaryl: The term “C₅₋₂₀haloaryl,” as used herein, describescertain C₅₋₂₀aryl groups which have been substituted with one or morehalo groups. Examples of such groups include, but are not limited to,halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, oriodophenyl, whether ortho-, meta-, or para-substituted), dihalophenyl,trihalophenyl, tetrahalophenyl, and pentahalophenyl.

Bidentate Substituents

The term “bidentate substituents,” as used herein, pertains tosubstituents which have two points of covalent attachment, and which actas a linking group between two other moieties.

In some cases (A), a bidentate substituent is covalently bound to asingle atom. In some cases (B), a bidentate substituent is covalentlybound to two different atoms, and so serves as a linking grouptherebetween.

Within (B), in some cases (C), a bidentate substituent is covalentlybound to two different atoms, which themselves are not otherwisecovalently linked (directly, or via intermediate groups). In some cases(D), a bidentate substituent is covalently bound to two different atoms,which themselves are already covalently linked (directly, or viaintermediate groups); in such cases, a cyclic structure results. In somecases, the bidentate group is covalently bound to vicinal atoms, thatis, adjacent atoms, in the parent group.

In some cases (A and D), the bidentage group, together with the atom(s)to which it is attached (and any intervening atoms, if present) form anadditional cyclic structure. In this way, the bidentate substituent maygive rise to a cyclic or polycyclic (e.g., fused, bridged, spiro)structure, which may be aromatic.

Examples of bidentate groups include, but are not limited to,C₁₋₇alkylene groups, C₃₋₂₀heterocyclylene groups, and C₅₋₂₀arylenegroups, and substituted forms thereof.

Alkylene

Alkylene: The term “alkylene,” as used herein, pertains to a bidentatemoiety obtained by removing two hydrogen atoms, either both from thesame carbon atom, or one from each of two different carbon atoms, of ahydrocarbon compound having from 1 to 20 carbon atoms (unless otherwisespecified), which may be aliphatic or alicyclic, and which may besaturated, partially unsaturated, or fully unsaturated. Thus, the term“alkylene” includes the sub-classes alkenylene, alkynylene,cycloalkylene, etc., discussed below.

In this context, the prefixes (e.g., C₁₋₄, C₁₋₇, C₁₋₂₀, C₂₋₇, C₃₋₇,etc.) denote the number of carbon atoms, or range of number of carbonatoms. For example, the term “C₁₋₄alkylene,” as used herein, pertains toan alkylene group having from 1 to 4 carbon atoms. Examples of groups ofalkylene groups include C₁₋₄alkylene (“lower alkylene”), C₁₋₇alkylene,and C₁₋₂₀alkylene.

Examples of linear saturated C₁₋₇alkylene groups include, but are notlimited to, —(CH₂)_(n)— where n is an integer from 1 to 7, for example,—CH₂— (methylene), —CH₂CH₂— (ethylene), —CH₂CH₂CH₂— (propylene), and—CH₂CH₂CH₂CH₂— (butylene).

Examples of branched saturated C₁₋₇alkylene groups include, but are notlimited to, —CH(CH₃>, —CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH(CH₂CH₃)—, —CH(CH₂CH₃)CH₂—, and—CH₂CH(CH₂CH₃)CH₂—.

Examples of linear partially unsaturated C₁₋₇alkylene groups include,but is not limited to, —CH═CH— (vinylene), —CH═CH—CH₂—, —CH═CH—CH₂—CH₂—,—CH═CH—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—, —CH═CH—CH═CH—CH₂—,—CH═CH—CH═CH—CH₂—CH₂—, —CH═CH—CH₂—CH═CH—, and —CH═CH—CH₂—CH₂—CH═CH—.

Examples of branched partially unsaturated C₁₋₇alkylene groups include,but is not limited to, —C(CH₃)—CH—, —C(CH₃)═CH—CH₂—, and—CH═CH—CH(CH₃)—.

Examples of alicyclic saturated C₁₋₇alkylene groups include, but are notlimited to, cyclopentylene (e.g., cyclopent-1,3-ylene), andcyclohexylene (e.g., cyclohex-1,4-ylene).

Examples of alicyclic partially unsaturated C₁₋₇alkylene groups include,but are not limited to, cyclopentenylene (e.g.,4-cyclopenten-1,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1,4-ylene;3-cyclohexen-1,2-ylene; 2,5-cyclohexadien-1,4-ylene).

Arylene

Arylene: The term “arylene,” as used herein, pertains to a bidentatemoiety obtained by removing two hydrogen atoms, one from each of twodifferent aromatic ring atoms of an aromatic compound, which moiety hasfrom 3 to 20 ring atoms (unless otherwise specified). Preferably, eachring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆arylene,” as usedherein, pertains to an arylene group having 5 or 6 ring atoms. Examplesof groups of arylene groups include C₃₋₂₀arylene, C₃₋₁₂arylene,C₅₋₁₂arylene, C₅₋₇arylene, and C₅₋₆arylene.

The ring atoms may be all-carbon atoms, as in “carboarylene groups”(e.g., C₅₋₂₀carboarylene).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroarylene groups” (e.g., C₅₋₂₀heteroarylene).

Examples of C₅₋₂₀arylene groups which do not have ring heteroatoms(i.e., C₅₋₂₀carboarylene groups) include, but are not limited to, thosederived from the compounds discussed above in regard to carboarylgroups.

Examples of C₅₋₂₀heteroarylene groups include, but are not limited to,those derived from the compounds discussed above in regard to heteroarylgroups.

Includes Other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.,asymmetric synthesis) and separation (e.g., fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form” is used herein in the conventional chemical sense andpertains to a compound in which one or more reactive functional groupsare protected from undesirable chemical reactions under specifiedconditions (e.g., pH, temperature, radiation, solvent, and the like). Inpractice, well known chemical methods are employed to reversibly renderunreactive a functional group, which otherwise would be reactive, underspecified conditions. In a chemically protected form, one or morereactive functional groups are in the form of a protected or protectinggroup (also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999).

A wide variety of such “protecting,” “blocking,” or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether, a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(-phenylsulphonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug,” as usedherein, pertains to a compound which, when metabolised (e.g., in vivo),yields the desired active compound. Typically, the prodrug is inactive,or less active than the active compound, but may provide advantageoushandling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

-   C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);-   C₁₋₇aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;    2-(4-morpholino)ethyl); and-   acyloxy-C₁₋₇alkyl-   (e.g., acyloxymethyl;-   acyloxyethyl;-   pivaloyloxymethyl;-   acetoxymethyl;-   1-acetoxyethyl;-   1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl;-   1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;-   1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;-   1-cyclohexyl-carbonyloxyethyl;-   cyclohexyloxy-carbonyloxymethyl;-   1-cyclohexyloxy-carbonyloxyethyl;-   (4-tetrahydropyranyloxy)carbonyloxymethyl;-   1-(4-tetrahydropyranyloxy)carbonyloxyethyl;-   (4-tetrahydropyranyl)carbonyloxymethyl; and-   1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu),iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex),phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy(MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

Synthesis

Methods for the chemical synthesis of compounds of the present inventionare described herein. These methods may be modified and/or adapted inknown ways in order to facilitate the synthesis of additional compoundswithin the scope of the present invention.

The compounds of the present invention may be prepared, for example, bythe methods described herein, or by adapting these or other well knownmethods in well known ways.

In one method, a suitable chloro sulfonate (also having a protectedcarboxylic acid group, e.g., ester) is prepared, for example, from analdehyde, by reaction with, e.g., H₂SO₄ and SO₃, followed by reactionwith, e.g., a suitable phosphate, e.g., (MeO)₂P(O)R, followed byreaction with, e.g., SO₂Cl₂. An example of such a method is illustratedin the following scheme.

The chloro sulfonate is then reacted with a suitable piperazine, to givethe corresponding piperazino sulfonamide. An example of such a method isillustrated in the following scheme (see also Method A below).

The protected carboxylic acid group (e.g., ester) is then converted to ahydroxamic acid, for example, by deprotection with NaOH, followed byreaction with (COCl)₂, followed by reaction with NH₂OH. An example ofsuch a method is illustrated in the following scheme (see also MethodsB, C, and D below).

In another method, a suitable phenylacrylic acid is reacted with, e.g.,chlorosulfonic acid (HSO₃Cl) to form the correspondingpara-chlorosulfonylphenyl acrylic acid, which is then reacted withpiperazine to form the corresponding piperazino sulfonamide. An exampleof such a method is illustrated in the following scheme.

The carboxylic acid group (e.g., ester) is then converted to achloroacyl group, for example, by reaction with (COCl)₂, and is thenconverted to a hydroxamic acid by reaction with, for example, NH₂OH. Anexample of such a method is illustrated in the following scheme.

In another method, suitable piperazine compounds are prepared byreaction of piperazine with a suitable carboxylic acid (R—COOH), forexample, in the presence of hydroxybenzotriazole, to give thecorresponding amide. An example of such a method is illustrated in thefollowing scheme (see also Method E below).

In another method, a suitably protected (e.g., t-butoxycarbonylprotected) piperazine is reacted with, for example, a haloacyl compound(e.g., chloroacylbenzene, PhCOCl) or a suitable carboxylic acid(R—COOH), to give the corresponding amide, followed by deprotection(e.g., with HCl/MeOH and NaOH). An example of such a method isillustrated in the following scheme (see also Methods F and G, below).

In another method, the piperazine amide is hydrogenated, for example, byreaction with LiAlH₄/THF, to give the corresponding N-substitutedpiperazine. An example of such a method is illustrated in the followingscheme (see also Method H below).

A number of N-substituted piperazine compounds are commerciallyavailable, and/or can be readily prepared using well known methods.Examples of such compounds include the following:

-   N-phenylpiperazine (17a);-   1-(diphenylmethyl)piperazine (17b);-   1-(2-methoxyphenyl)piperazine hydrochloride (17c);-   1-(2-chlorophenyl)piperazine (17d);-   1-(3-chlorophenyl)piperazine (17e);-   1-(4-methoxyphenyl)piperazine (17f);-   1-(3-methoxyphenyl)piperazine (17g);-   1-(4-nitrophenyl)piperazine (17h);-   1-(3,4-dichlorophenyl)piperazine (17i);-   1-(4-fluorophenyl)piperazine (17j);-   1-(4-chlorophenyl)piperazine (17k);-   1-(2-pyridinyl)piperazine (17l);-   2-(1-piperazinyl)pyrimidine (17m); and-   1-(3,4-dimethylphenyl)piperazine (17n).

In another method, a suitable carboxylic acid (also having a protectedcarboxylic acid group) is reacted with a suitable piperazine, forexample, in the presence of carbonyldiimidazole (CDI). An example ofsuch a method is illustrated in the following scheme (see also MethodsJ, K, and L, below).

The protected carboxylic acid group (e.g., ester) is then converted to ahydroxamic acid, for example, by reaction with NH₂OH and NaOMe inmethanol. An example of such a method is illustrated in the followingscheme (see also Methods Q and R, below).

In another method, a suitable carboxylic acid (also having a protectedcarboxylic acid group) is reacted with (COCl)₂ and H₂NOBn, to give thecorresponding benzyloxyamide. The protected carboxylic acid group isthen deprotected, for example, by reaction with NaOH, and then reactedwith a suitable piperazine to give the corresponding piperazine amide.The benzyloxyamide is then converted to a carbamic acid, for example, byreaction with H₂ over Pd(C). An example of such a method is illustratedin the following scheme (see also Methods M, N, P, and S, below).

Use

The present invention provides active compounds, specifically, activecarbamic acids, as described herein.

The term “active,” as used herein, specifically includes both compoundswith intrinsic activity (drugs) as well as prodrugs of such compounds,which prodrugs may themselves exhibit little or no intrinsic activity.

The present invention also provides active compounds which inhibit HDACactivity.

The present invention also provides methods of inhibiting HDAC in acell, comprising contacting said cell with an effective amount of anactive compound. Such a method may be practised in vitro or in vivo. Inone embodiment, the method is performed in vitro. In one embodiment, themethod is performed in vivo. Preferably, the active compound is providedin the form of a pharmaceutically acceptable composition.

The term “inhibiting HDAC,” as used herein, includes: inhibiting HDACactivity; inhibiting the formation of HDAC complexes; and inhibiting theactivity of HDAC complexes.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound inhibits HDAC activity. For example, one assaywhich may conveniently be used in order to assess the HDAC inhibitionoffered by a particular compound is described in the examples below.

The present invention also provides active compounds which (a) regulate(e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression;(c) promote apoptosis; or (d) a combination of one or more of these.

Thus, the present invention also provides methods of (a) regulating(e.g., inhibiting) cell proliferation; (b) inhibiting cell cycleprogression; (c) promoting apoptosis; or (d) a combination of one ormore of these, in vitro or in vivo, comprising contacting a cell with aneffective amount of an active compound, as described herein.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound regulate (e.g., inhibit) cell proliferation,etc. For example, assays which may conveniently be used to assess theactivity offered by a particular compound are described in the examplesbelow.

For example, a sample of cells (e.g., from a tumour) may be grown invitro and an active compound brought into contact with said cells, andthe effect of the compound on those cells observed. As an example of“effect,” the morphological status of the cells (e.g., alive or dead,etc.) may be determined. Where the active compound is found to exert aninfluence on the cells, this may be used as a prognostic or diagnosticmarker of the efficacy of the compound in methods of treating a patientcarrying cells of the same cellular type.

Methods of Treatment, Etc.

The invention further provides methods of treatment, comprisingadministering to a subject in need of treatment atherapeutically-effective amount of an active compound, preferably inthe form of a pharmaceutical composition.

The invention further provides active compounds for use in a method oftreatment of the human or animal body by therapy, for example, in thetreatment of a condition mediated by HDAC, a condition known to betreated by HDAC inhibitors (such as, e.g., trichostatin A), cancer, aproliferative condition, or other condition as described herein.

The invention further provides the use of an active compound for themanufacture of a medicament, for example, for the treatment of acondition mediated by HDAC, a condition known to be treated by HDACinhibitors (such as, e.g., trichostatin A), cancer, a proliferativecondition, or other condition as described herein.

Treatment

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.,prophylaxis) is also included.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosageform comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio.

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. Examples of treatments and therapiesinclude, but are not limited to, chemotherapy (the administration ofactive agents, including, e.g., drugs, antibodies (e.g., as inimmunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT,ADEPT, etc.); surgery; radiation therapy; and gene therapy.

Active compounds may also be used, as described above, in combinationtherapies, that is, in conjunction with other agents, for example,cytotoxic agents.

Anti-HDAC Applications

The present invention also provides active compounds which are anti-HDACagents, and which treat a condition mediated by HDAC.

The term “a condition mediated by HDAC,” as used herein pertains to acondition in which HDAC and/or the action of HDAC is important ornecessary, e.g., for the onset, progress, expression, etc. of thatcondition, or a condition which is known to be treated by HDACinhibitors (such as, e.g., trichostatin A).

Examples of such conditions include, but are not limited to, thefollowing:

-   Cancer (see, e.g., Vigushin et al., 2001).-   Psoriasis (see, e.g., lavarone et al., 1999).-   Fibroproliferative disorders (e.g., liver fibrosis) (see, e.g., Niki    et al., 1999; Corneil et al., 1998).-   Smooth muscle proliferative disorder (e.g., atherosclerosis,    restenosis) (see, e.g., Kimura et al., 1994).-   Neurodegenative diseases (e.g., Alzheimer's, Parkinson's,    Huntington's chorea, amyotropic lateral sclerosis, spino-cerebellar    degeneration) (see, e.g., Kuusisto et al., 2001).-   Inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis)    (see, e.g., Dangond et al., 1998; Takahashi et al., 1996).-   Diseases involving angiogenesis (e.g., cancer, rheumatoid arthritis,    psoriasis, diabetic retinopathy) (see, e.g., Kim et al., 2001).-   Haematopoietic disorders (e.g., anaemia, sickle cell anaemia,    thalassaeimia) (see, e.g., McCaffrey et al., 1997).-   Fungal infection (see, e.g., Bernstein et al., 2000; Tsuji et al.,    1976).-   Parasitic infection (e.g., malaria, trypanosomiasis, helminthiasis,    protozoal infections (see, e.g., Andrews et al., 2000).-   Bacterial infection (see, e.g., Onishi et al., 1996).-   Viral infection (see, e.g., Chang et al., 2000).

Conditions treatable by immune modulation (e.g., multiple sclerosis,autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma,allergic rhinitis, inflammatory bowel disease; and for improvinggrafting of transplants) (see, e.g., Dangond et al., 1998; Takahashi etal., 1996).

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a condition mediated by HDAC for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

Anticancer Applications

The present invention also provides active compounds which areanticancer agents, and treat cancer.

Thus, the present invention also provides methods of treating cancer,comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein, preferably in the form of a pharmaceutical composition.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a cancerous condition for any particularcell type. For example, assays which may conveniently be used to assessthe activity offered by a particular compound are described in theexamples below.

The term “anticancer agent” as used herein, pertains to a compound whichtreats a cancer (i.e., a compound which is useful in the treatment of acancer). The anti-cancer effect may arise through one or moremechanisms, including but not limited to, the regulation of cellproliferation, the inhibition of cell cycle progression, the inhibitionof angiogenesis (the formation of new blood vessels), the inhibition ofmetastasis (the spread of a tumour from its origin), the inhibition ofinvasion (the spread of tumour cells into neighbouring normalstructures), or the promotion of apoptosis (programmed cell death).Examples of cancers are discussed below.

Antiproliferative Applications

The present invention also provides active compounds which areantiproliferative agents. The term “antiproliferative agent” as usedherein, pertain to a compound which treats a proliferative condition(i.e., a compound which is useful in the treatment of a proliferativecondition).

Thus, the present invention also provides methods of treating aproliferative condition, comprising administering to a subject in needof treatment a therapeutically-effective amount of an active compound,as described herein, preferably in the form of a pharmaceuticalcomposition.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a proliferative condition for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

The terms “cell proliferation,” “proliferative condition,”“proliferative disorder,” and “proliferative disease,” are usedinterchangeably herein and pertain to an unwanted or uncontrolledcellular proliferation of excessive or abnormal cells which isundesired, such as, neoplastic or hyperplastic growth, whether in vitroor in vivo.

Examples of proliferative conditions include, but are not limited to,benign, pre-malignant, and malignant cellular proliferation, includingbut not limited to, neoplasms and tumours (e.g., histocytoma, glioma,astrocyoma, osteoma), cancers (e.g., lung cancer, small cell lungcancer, gastrointestinal cancer, bowel cancer, colon cancer, breastcarinoma, ovarian carcinoma, prostate cancer, testicular cancer, livercancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer,sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias,psoriasis, bone diseases, fibroproliferative disorders (e.g., ofconnective tissues), and atherosclerosis.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g., bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

Additional Uses

Active compounds may also be used as cell culture additives to inhibitHDAC, for example, in order to regulate (e.g., inhibit) cellproliferation in vitro.

Active compounds may also be used as part of an in vitro assay, forexample, in order to determine whether a candidate host is likely tobenefit from treatment with the compound in question.

Active compounds may also be used as a standard, for example, in anassay, in order to identify other active compounds, other HDACinhibitors, other anticancer agents, other antiproliferative agents,etc.

The compounds of the present invention may also be used in methods ofimproving protein production by cultured cells (see, e.g., Furukawa etal., 1998).

Routes of Administration

The active compound or pharmaceutical composition comprising the activecompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject

The subject may be a prokaryote (e.g., bacteria) or a eukaryote (e.g.,protoctista, fungi, plants, animals).

The subject may be a protoctista, an alga, or a protozoan.

The subject may be a plant, an angiosperm, a dicotyledon, amonocotyledon, a gymnosperm, a conifer, a ginkgo, a cycad, a fern, ahorsetail, a clubmoss, a liverwort, or a moss.

The subject may be an animal.

The subject may be a chordate, an invertebrate, an echinoderm (e.g.,starfish, sea urchins, brittlestars), an arthropod, an annelid(segmented worms) (e.g., earthworms, lugworms, leeches), a mollusk(cephalopods (e.g., squids, octopi), pelecypods (e.g., oysters, mussels,clams), gastropods (e.g., snails, slugs)), a nematode (round worms), aplatyhelminthes (flatworms) (e.g., planarians, flukes, tapeworms), acnidaria (e.g., jelly fish, sea anemones, corals), or a porifera (e.g.,sponges).

The subject may be an arthropod, an insect (e.g., beetles, butterflies,moths), a chilopoda (centipedes), a diplopoda (millipedes), a crustacean(e.g., shrimps, crabs, lobsters), or an arachnid (e.g., spiders,scorpions, mites).

The subject may be a chordate, a vertebrate, a mammal, a bird, a reptile(e.g., snakes, lizards, crocodiles), an amphibian (e.g., frogs, toads),a bony fish (e.g., salmon, plaice, eel, lungfish), a cartilaginous fish(e.g., sharks, rays), or a jawless fish (e.g., lampreys, hagfish).

The subject may be a mammal, a placental mammal, a marsupial (e.g.,kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent(e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse),a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., adog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., apig) ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian(e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape(e.g., gorilla, chimpanzee, orangutan, gibbon), or a human.

Furthermore, the subject may be any of its forms of development, forexample, a spore, a seed, an egg, a larva, a pupa, or a foetus.

Formulations

While it is possible for the active compound to be used (e.g.,administered) alone, it is often preferable to present it as aformulation.

Thus, one aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a carrier.

In one embodiment, the composition is a pharmaceutical composition(e.g., formulation, preparation, medicament) comprising a compound, asdescribed herein, and a pharmaceutically acceptable carrier.

In one embodiment, the composition is a pharmaceutical compositioncomprising at least one compound, as described herein, together with oneor more other pharmaceutically acceptable ingredients well known tothose skilled in the art, including, but not limited to,pharmaceutically acceptable carriers, diluents, excipients, adjuvants,fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents,colouring agents, flavouring agents, and sweetening agents.

In one embodiment, the composition further comprises other activeagents, for example, other therapeutic or prophylactic agents.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts. See, for example, Handbook of PharmaceuticalAdditives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (SynapseInformation Resources, Inc., Endicott, N.Y., USA), Remington'sPharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton,Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

Another aspect of the present invention pertains to methods of making apharmaceutical composition comprising admixing at least one activecompound, as defined above, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, e.g., carriers, diluents, excipients, etc. If formulated asdiscrete units (e.g., tablets, etc.), each unit contains a predeterminedamount (dosage) of the active compound.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive compound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with carriers(e.g., liquid carriers, finely divided solid carrier, etc.), and thenshaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, losenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or moreactive compounds and optionally one or more other pharmaceuticallyacceptable ingredients, including, for example, penetration, permeation,and absorption enhancers. Formulations may also suitably be provided ina the form of a depot or reservoir.

The active compound may be dissolved in, suspended in, or admixed withone or more other pharmaceutically acceptable ingredients. The activecompound may be presented in a liposome or other microparticulate whichis designed to target the active compound, for example, to bloodcomponents or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the active compound in aflavored basis, usually sucrose and acacia or tragacanth. Pastillestypically comprise the active compound in an inert matrix, such asgelatin and glycerin, or sucrose and acacia. Mouthwashes typicallycomprise the active compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the active compoundin a free-flowing form such as a powder or granules, optionally mixedwith one or more binders (e.g., povidone, gelatin, acacia, sorbitol,tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g.,lactose, microcrystalline cellulose, calcium hydrogen phosphate);lubricants (e.g., magnesium stearate, talc, silica); disintegrants(e.g., sodium starch glycolate, cross-linked povidone, cross-linkedsodium carboxymethyl cellulose); surface-active or dispersing or wettingagents (e.g., sodium lauryl sulfate); preservatives (e.g., methylp-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours,flavour enhancing agents, and sweeteners. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active compound therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the active compound and aparaffinic or a water-miscible ointment base.

Creams are typically prepared from the active compound and anoil-in-water cream base. If desired, the aqueous phase of the cream basemay include, for example, at least about 30% w/w of a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active compound through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogues.

Emulsions are typically prepared from the active compound and an oilyphase, which may optionally comprise merely an emulsifier (otherwiseknown as an emulgent), or it may comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabiliser. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabiliser(s) make up the so-called emulsifying wax, and the waxtogether with the oil and/or fat make up the so-called emulsifyingointment base which forms the oily dispersed phase of the creamformulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulphate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the active compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the active compound is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active compound, such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the activecompound is dissolved, suspended, or otherwise provided (e.g., in aliposome or other microparticulate). Such liquids may additional containother pharmaceutically acceptable ingredients, such as anti-oxidants,buffers, preservatives, stabilisers, bacteriostats, suspending agents,thickening agents, and solutes which render the formulation isotonicwith the blood (or other relevant bodily fluid) of the intendedrecipient. Examples of excipients include, for example, water, alcohols,polyols, glycerol, vegetable oils, and the like. Examples of suitableisotonic carriers for use in such formulations include Sodium ChlorideInjection, Ringer's Solution, or Lactated Ringer's Injection. Typically,the concentration of the active compound in the liquid is from about 1ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1μg/ml. The formulations may be presented in unit-dose or multi-dosesealed containers, for example, ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the active compounds, and compositions comprising the activecompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, the severity of the condition, and thespecies, sex, age, weight, condition, general health, and prior medicalhistory of the patient. The amount of compound and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the active compound is in the range ofabout 0.1 to about 250 mg per kilogram body weight of the subject perday. Where the active compound is a salt, an ester, an amide, a prodrug,or the like, the amount administered is calculated on the basis of theparent compound and so the actual weight to be used is increasedproportionately.

Kits

One aspect of the invention pertains to a kit comprising (a) the activeingredient, preferably provided in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions on how to administer the active compound, etc.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

EXAMPLES

The following are examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

General

¹H NMR spectra were recorded at ambient temperature with WH-90/DS orMercury 200 (Varian) spectrometers. The HPLC measurements were performedon a Gilson Model 302 system equipped with a spectrophotometer.Elemental analyses were obtained with a Carlo Erba EA 1108 instrument.Melting points were measured on a “Boëtius” micro melting pointapparatus and are uncorrected. Silicagel, 0.035-0.070 mm, (Acros) wasemployed for column chromatography. All the solvents were purifiedbefore use by routine techniques. To isolate reaction products thesolvents were removed by evaporation using a vacuum rotary evaporator,the water bath temperature not exceeding 40° C.

Various reagents were purchased from Sigma-Aldrich (The Old Brickyard,New Road, Gillingham, Dorset, UK), Acros Organics (JanssensPharmaceuticalaan 3A, 2440 Geel, Belgium), Lancaster Synthesis Ltd.(Eastgate, White Lund, Morecambe, Lancashire, LA3 3DY, UK), and BapeksLtd. (Riga, Latvia).

Example 1 3-Formylbenzenesulfonic acid, Sodium Salt (1)

Oleum (5 mL) was placed in a reaction vessel and benzaldehyde (2.00 g,18.84 mmol) was slowly added not exceeding the temperature of thereaction mixture more than 30° C. The obtained solution was stirred at40° C. for 10 hours and at ambient temperature overnight. The reactionmixture was poured into ice and extracted with ethyl acetate. Theaqueous phase was treated with CaCO₃ until the evolution of CO₂ ceased(pH˜6-7), then the precipitated CaSO₄ was filtered off and washed withwater. The filtrate was treated with Na₂CO₃ until the pH of the reactionmedium increased to pH 8, obtained CaCO₃ was filtered off and watersolution was evaporated in vacuum. The residue was washed with methanol,the washings were evaporated and the residue was dried in desiccatorover P₂O₅ affording the title compound (2.00 g, 51%). ¹H NMR (D₂O), δ:7.56-8.40 (4H, m); 10.04 (1H, s).

Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, Sodium Salt (2)

Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol),potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate(1.05 g, 5.77 mmol) and water (2 mL) were stirred at ambient temperaturefor 30 min, and the precipitated solid was filtered and washed withmethanol. The filtrate was evaporated and to give the title compound asa white solid (0.70 g, 55%). ¹H NMR (DMSO-d₆, HMDSO), δ: 3.68 (3H, s);6.51 (1H, d, J=16.0 Hz); 7.30-7.88 (5H, m).

Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)

To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2)(0.670 g, 2.53 mmol) benzene (2 mL), thionyl chloride (1.508 g, 0.9 mL,12.67 mmol) and 3 drops of dimethylformamide were added and theresultant suspension was stirred at reflux for one hour. The reactionmixture was evaporated, the residue was dissolved in benzene (3 mL),filtered and the filtrate was evaporated to give the title compound(0.640 g, 97%).

Method A—General Synthesis of methyl (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoates (4a-l)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3)(0.40 g, 1.53 mmol) in dioxane (5.0 mL) was added to a mixture ofappropriate piperazine (1.53 mmol) in dioxane (2.0 mL) and NaHCO₃ (0.26g, 3.06 mmol) in water (3.0 mL) (in the case of piperazinehydrochlorides the amount of NaHCO₃ was increased by 1 eq), and theresultant solution was stirred at room temperature until initialcompounds disappeared (1-2 hours). Water was added to the reactionmixture. In the case of a precipitate formation, it was filtered, washedwith water, ether, and dried to give the corresponding methyl(E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4). Otherwise, the reaction mixture was extracted with ethyl acetate,washed successively with water, brine, dried (Na₂SO₄), and solventremoved to give the corresponding methyl (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4).

Example 4 Methyl(E)-3-(3-{[4-phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4a)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-phenylpiperazine, using Method A, yield 84%.¹H NMR (DMSO-d₆, HMDSO), δ: 2.94-3.39 (8H, m); 3.74 (3H, s); 6.65-7.03(4H, m); 7.05-7.32 (2H, m); 7.60-7.92 (3H, m); 7.94-8.20 (2H, m).

Example 5 Methyl(E)-3-(3-{[4-benzhydryl-1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4b)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-benzhydrylpiperazine, using Method A, yield96%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.16-2.60 (4H, m); 2.78-3.07 (4H, m);3.78 (3H, s); 4.32 (1H, s); 6.73 (1H, d, J=16.0 Hz); 7.12-8.27 ppm (15H,m).

Example 6 Methyl(E)-3-(3-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4c)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(2-methoxyphenyl)-piperazine hydrochloride,using Method A, yield 87%. ¹H NMR (CDCl₃, HMDSO), δ: 3.03-3.29 (8H, m);3.78 (3H, s); 3.83 (3H, s); 6.48 (1H, d, J=16.0 Hz); 6.76-7.07 (4H, m);7.42-7.94 (4H, m); 7.72 ppm (1H, d, J=16.0 Hz).

Example 7 Methyl(E)-3-(3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4d)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(2-chlorophenyl)-piperazine hydrochloride,using Method A, yield 81%. ¹H NMR (CDCl₃, HMDSO), δ: 2.94-3.38 (8H, m);3.85 (3H, s); 6.54 (1H, d, J=16.0 Hz); 6.87-7.43 (3H, m); 7.12 (1H, d,J=16.0 Hz); 7.42-7.94 ppm (5H, m).

Example 8 Methyl(E)-3-(3-{[4-(3-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4e)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(3-chlorophenyl)-piperazine hydrochloride,using Method A, yield 71%. ¹H NMR (CDCl₃, HMDSO), δ: 2.94-3.45 (8H, m);3.83 (3H, s); 6.56 (1H, d, J=116.0 Hz); 6.60-6.98 (3H, m); 7.16 (1H, d,J=16.0 Hz); 7.45-8.05 ppm (5H, m).

Example 9 Methyl(E)-3-(3-{[4-(2-pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4f)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(2-pyridyl)piperazine, using Method A, yield82%. ¹H NMR (CDCl₃, HMDSO), δ: 2.94-3.25 (4H, m); 3.43-3.72 (4H, m);3.78 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.47-6.72 (2H, m); 7.27-7.94 (6H,m); 8.00-8.20 ppm (1H, m).

Example 10 Methyl(E)-3-(3-{[4-(4-acetylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4g)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 4′-piperazinoacetophenone, using Method A,yield 90%. ¹H NMR (DMSO-d₆ HMDSO), δ: 2.45 (3H, s); 2.94-3.25 (4H, m);3.32-3.65 (4H, m, overlapped with a signal of water); 3.78 (3H, s); 6.85(1H, d, J=16.0 Hz); 6.86-7.16 (2H, m); 7.65-7.96 (5H, m); 8.05-8.27 ppm(2H, m).

Example 11 Methyl(E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4h)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(4-dimethylaminophenetyl)piperazine, usingMethod A, yield 91%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.14-2.63 (8H, m,overlapped with a signal of DMSO); 2.80 (6H, s); 2.81-3.05 (4H, m); 3.78(3H, s); 6.63 (2H, d, J=9.4 Hz); 6.84 (1H, d, J=16.0 Hz); 7.00 (2H, d,J=9.4 Hz); 7.61-7.88 (2H, m); 7.83 (1H, d, J=16.0 Hz); 7.99-8.28 ppm(2H, m).

Example 12 Methyl(E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4i)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-[2-(1-naphthyloxy)ethyl]piperazine, usingMethod A, yield 78%. ¹H NMR (DMSO-d₆. HMDSO), δ: 2.36-2.77 (8H, m,overlapped with a signal of DMSO); 2.78-3.09 (4H, m); 3.72 (3H, s); 6.76(1H, d, J=15.7 Hz); 7.20-7.53 (3H, m); 7.54-7.94 (7H, m); 7.96-8.20 ppm(2H, m).

Example 13 Methyl(E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4j)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-[2-(2-naphthyloxy)ethyl]piperazine, usingMethod A, yield 94%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.38-2.65 (6H, m,overlapped with a signal of DMSO); 2.76 (2H, t, J=5.0 Hz); 2.83-3.05(2H, m); 3.71 (3H, s); 4.11 (2H, t, J=5.3 Hz); 6.76 (1H, d, J=16.0 Hz);6.98-7.56 (4H, m); 7.60-7.92 (6H, m); 7.93-8.18 ppm (2H, m).

Example 14 Methyl(E)-3-(3-{[4-(3,4-dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4k)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(3,4-dichlorophenyl)-piperazine, usingMethod A, yield 85%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.76-3.12 (4H, m);3.13-3.38 (4H, m, overlapped with a signal of water); 3.66 (3H, s); 6.76(1H, d, J=15.9 Hz); 6.87 (1H, dd, J=2.8 and 8.4 Hz); 7.10 (1H, d, J=2.8Hz); 7.38 (1H, d, J=8.4 Hz); 7.78 (1H, d, J=15.9 Hz); 7.60-7.93 (2H, m);7.95-8.27 ppm (2H, m).

Example 15 Methyl(E)-3-(3-{[4-(4-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4l)

The title compound was obtained from 3-(3-chlorosulfonylphenyl)acrylicacid methyl ester (3) and 1-(4-chlorophenyl)-piperazine, using Method A,yield 84%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.76-3.34 (8H, m); 3.72 (3H, s);6.80 (1H, d, J=15.9 Hz); 6.92 (2H, d, J=8.9 Hz); 7.23 (2H, d, J=8.9 Hz);7.80 (1H, d, J=15.9 Hz); 7.56-7.96 (2H, m); 7.98-8.25 ppm (2H, m).

Method B—General Synthesis of (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl-2-propenoic acids (5a-l)

To a suspension or solution of appropriate methyl(E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4a-l) (1.29 mmol) in methanol-tetrahydrofuran (2:3) mixture (5.0 mL),1N NaOH solution (3.87 mL, 3.87 mmol) was added and the resultantmixture was stirred at ambient temperature overnight. The reactionmixture was partitioned between ethyl acetate and water. The aqueouslayer was acidified with 1 N KH₂PO₄ solution. In the case of aprecipitate formation, it was filtered, washed with water, ether (orother suitable solvent), and dried to give the corresponding(E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid(5). Otherwise, the reaction mixture was extracted with ethyl acetate,washed successively with water, brine, dried (Na₂SO₄), and solventremoved to give the corresponding (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5).

Example 16(E)-3-(3-{[4-Phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5a)

The title compound was obtained from methyl(E)-3-(3-{[4-phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4a) asa white solid, using Method B, yield 61%. ¹H NMR (DMSO-d₆, HMDSO), δ:2.87-3.65 (8H, m); 6.54-6.98 (4H, m); 7.00-7.36 (2H, m); 7.58-7.92 (3H,m); 7.94-8.23 (2H, m).

Example 17 (E)-3-(3-[{4-Benzhydryl-1piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5b)

The title compound was obtained from methyl(E)-3-(3-{[4-benzhydryl-1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4b)as a white solid, using Method B, yield 70%. ¹H NMR (DMSO-d₆ HMDSO), δ:2.20-2.56 (4H, m); 2.80-3.07 (4H, m); 4.27 (1H, s); 6.67 (1H, d, J=16.0Hz); 7.05-8.16 ppm (15H, m).

Example 18(E)-3-(3-{[4-(2-Methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5c)

The title compound was obtained from methyl(E)-3-(3-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4c) as a white solid, using Method B, yield 84%. ¹H NMR (DMSO-d₆,HMDSO), δ: 2.76-3.25 (8H, m); 3.72 (3H, s); 6.74 (1H, d, J=16.0 Hz);6.76-7.14 (4H, m); 7.60-7.94 (2H, m); 7.76 (1H, d, J=16.0 Hz); 7.94-8.27ppm (2H, m).

Example 19(E)-3-(3-{[4-(2-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5d)

The title compound was obtained from methyl(E)-3-(3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(d), using Method B, yield 83%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.72-3.27(8H, m); 6.72 (1H, d, J=16.0 Hz); 6.89-7.52 (4H, m); 7.60-7.92 (2H, m);7.74 (1H, d, J=16.0 Hz); 7.96-8.25 ppm (2H, m).

Example 20(E)-3-(3-{[443-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5e)

The title compound was obtained from methyl(E)-3-(3-{[4-(3-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4e), using Method B, yield 89%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.87-3.16(6H, m); 3.17-3.67 (2H, m, overlapped with a signal DMSO); 6.67 (1H, d,J=16.0 Hz); 6.68-7.00 (3H, m); 7.02-7.34 (1H, m); 7.56-7.87 (2H, m);7.72 (1H, d, J=16.0 Hz); 7.94-8.23 ppm (2H, m).

Example 21(E)-3-(3-{[4-(2-Pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5f)

The title compound was obtained from methyl(E)-3-(3-{[4-(2-pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4f) using Method B, yield 91%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.83-3.14(4H, m); 3.43-3.69 (4H, m); 6.52-6.89 (2H, m); 6.67 (1H, d, J=16.0 Hz);7.36-7.83 (3H, m); 7.69 (1H, d, J=16.0 Hz); 7.94-8.18 ppm (3H, m).

Example 22

(E)-3-(3-{[4-(4-Acetylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5g)

The title compound was obtained from methyl(E)-3-(3-{[4-(4-acetylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4g), using Method B, yield 85%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.38 (3H,s); 2.89-3.20 (4H, m); 3.21-3.67 (4H, m, overlapped with a signal ofwater); 6.69 (1H, d, J=16.0 Hz); 6.70-7.11 (2H, m); 7.53-7.94 (5H, m);7.96-8.20 ppm (2H, m).

Example 23

(E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5h)

The title compound was obtained from methyl(E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4h), using Method B, yield 80%. ¹H NMR (DMSO-d₆ HMDSO), δ: 2.23-2.67(8H, m, overlapped with a signal of DMSO); 2.80 (6H, s); 2.72-3.09 (4H,m); 6.63 (2H, d, J=8.0 Hz); 6.74 (1H, d, J=16.0 Hz); 6.99 (2H, d, J=8.0Hz); 7.51-7.89 (3H, m); 7.90-8.32 ppm (2H, m).

Example 24

(E)-3-[3-({4-[2-(1-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5i)

The title compound was obtained from methyl(E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4i), using Method B, yield 90%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.36-2.76(6H, m, overlapped with a signal of DMSO); 2.78-3.07 (6H, m); 6.69 (1H,d, J=15.7 Hz); 7.22-7.56 (3H, m); 7.58-7.92 (7H, m); 7.93-8.16 ppm (2H,m).

Example 25(E)-3-[3-({4-[2-(2-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5j)

The title compound was obtained from methyl(E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate(4j), using Method B, yield 84%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.36-2.58(6H, m, overlapped with a signal of DMSO); 2.76 (2H, t, J=5.0 Hz);2.82-3.05 (2H, m); 4.11 (2H, t, J=5.3 Hz); 6.67 (1H, d, J=16.0 Hz);6.98-7.52 (4H, m); 7.53-7.87 (6H, m); 7.88-8.16 ppm (2H, m).

Example 26

(E)-3-(3-{[4-(3,4-Dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5k)

The title compound was obtained from methyl(E)-3-(3-{[4-(3,4-dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(4k), using Method B, yield 87%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.69-3.1.6(4H, m); 3.17-3.47 (4H, m); 6.69 (1H, d, J=116.0 Hz); 6.92 (1H, dd,J=2.8 and 8.4 Hz); 7.13 (1H, d, J=2.8 Hz); 7.38 (1H, d, J=8.4 Hz); 7.54(1H, d, J=16.0 Hz); 7.58-7.92 (2H, m); 7.93-8.18 ppm (2H, m).

Example 27

(E)-3-(3-{[4-(4-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5l)

The title compound was obtained from methyl(E)-3-(3-{[4-(4-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoate(41), using Method B, yield 75%. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.83-3.49(8H, m, overlapped with a signal of water); 6.67 (1H, d, J=15.9 Hz);6.89 (1H, d, J=8.9 Hz); 7.18 (2H, d, J=8.9 Hz); 7.49-7.87 (2H, m); 7.69(1H, d, J=15.9 Hz); 7.88-8.20 ppm (2H, m).

Method C—General Synthesis of (E)-3-(3-{[substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chlorides (6a-l)

To a suspension of appropriate (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5a-l) (0.78 mmol) indichloromethane (4.0 mL) oxalyl chloride (0.21 mL, 2.37 mmol) and onedrop of dimethylformamide were added. The reaction mixture was stirredat 40° C. for one hour and concentrated under reduced pressure to givecrude (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6).

Example 28(E)-3-(3-{[4-Phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride(6a)

The title compound was obtained from(E)-3-(3-{[4-phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid(5a), using Method C, in a form of a crude product.

Example 29(E)-3-(3-{[4-Benzhydryl-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6b)

The title compound was obtained from(E)-3-(3-{[4-benzhydryl-1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid(5b), using Method C, in a form of a crude product.

Example 30(E)-3-(3-{[4-(2-Methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6c)

The title compound was obtained from(E)-3-(3-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (i), using Method C, in a form of a crude product.

Example 31(E)-3-(3-{[4-(2-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6d)

The title compound was obtained from(E)-3-(3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5d), using Method C, in a form of a crude product.

Example 32(E)-3-(3-{[4-(3-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6e)

The title compound was obtained from(E)-3-(3-{[4-(3-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5e), using Method C, in a form of a crude product.

Example 33(E)-3-(3-{[4-(2-Pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6f)

The title compound was obtained from(E)-3-(3-{[4-(2-pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5f), using Method C, in a form of a crude product.

Example 34(E)-3-[3-({4-[4-(1-Chlorovinyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6g)

The title compound was obtained from(E)-3-(3-{[4-(4-acetylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5g), using Method C, in a form of a crude product.

Example 35(E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6h)

The title compound was obtained from(E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5h), using Method C, in a form of a crude product.

Example 36(E)-3-[3-({4-[2-(1-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6i)

The title compound was obtained from(E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5i), using Method C, in a form of a crude product.

Example 37(E)-3-[3-({4-[2-(2-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6j)

The title compound was obtained from(E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (5j), using Method C, in a form of a crude product.

Example 38(E)-3-(3-{[4-(3,4-Dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6k)

The title compound was obtained from(E)-3-(3-{[4-(3,4-dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5k), using Method C, in a form of a crude product.

Example 39(E)-3-(3-{[4-(4-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6l)

The title compound was obtained from(E)-3-(3-{[4-(4-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoicacid (5l), using Method C, in a form of a crude product.

Method D—General Synthesis of (E)-N-hydroxy-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenamides

To a suspension of hydroxylamine hydrochloride (0.27 g, 3.90 mmol) intetrahydrofuran (6.0 mL) a saturated NaHCO₃ solution (6.9 mL) was addedand the resultant mixture was stirred at ambient temperature for 10minutes. To the reaction mixture an appropriate (E)-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6a-l) (ca. 0.78mmol) solution in tetrahydrofuran (4.0 mL) was added and the obtainedmixture was stirred at ambient temperature for ca. one hour. The organiclayer was separated, the water layer was supplemented with water (ca. 5mL) and extracted with ethyl acetate. The organic extracts werecombined, washed successively with water, brine, and dried (Na₂SO₄). Thesolvent was removed and the crude product was washed with an appropriatesolvent (ether, methanol, ethyl acetate, acetonitrile etc.) orcrystallized from ether, methanol, ethyl acetate or acetonitrile, ortheir mixtures to give the corresponding target(E)-N-hydroxy-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenamide. Otherwise, the crudereaction product was chromatographed on silica gel withchloroform-methanol as eluents to give the corresponding(E)-N-hydroxy-3-(3-{[4-substituted1-piperazinyl]sulfonyl}phenyl)-2-propenamide.

Example 40(E)-N-Hydroxy-3-{3-[(4-phenyl-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118490)

The title compound was obtained from(E)-3-(3-{[4-phenyl-1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride(6a) as white crystals, using Method D, yield 73% (on 5a). M.p. 201° C.¹H NMR (DMSO-d₆, HMDSO), δ: 2.91-3.39 (8H, m, overlapped with a signalof water); 6.62 (1H, d, J=16.0 Hz); 6.74-6.99 (3H, m); 7.06-7.34 (2H,m); 7.57 (1H, d, J=16.0 Hz); 7.56-8.12 (4H, m); 9.11 (1H, brs); 10.79(1H, s). HPLC analysis on Zorbax SB-C₁₈ column: impurities 1.3% (columnsize 4.6×150 mm; mobile phase acetonitrile-0.1% H₃PO₄, gradient from50:50 to 100:0; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min.;detector: UV 254 nm). Anal. Calcd for C₁₉H₂₁N₃O₄S, %: C, 58.90; H, 5.46;N, 10.84. Found, %: C, 58.73; H, 5.34; N, 10.69.

Example 41(E)-N-Hydroxy-3-{3-[(4-benzhydryl-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118491)

The Title Compound was obtained from(E)-3-(3-{[4-Benzhydryl-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6b) as white crystals, using Method D, yield 57% (on 5b). M.p.156° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.18-2.54 (4H, m, overlapped with asignal of DMSO); 2.75-3.11 (4H, m); 4.31 (1H, s); 6.64 (1H, d, J=116.0Hz); 7.01-8.11 (15H, m); 9.15 (1H, brs); 10.83 (1H, s). HPLC analysis onSymmetry C₁₈ column: impurities 7% (column size 3.9×150 mm; mobile phaseacetonitrile-0.1M phosphate buffer (pH 2.5), 50:50; sample concentration1 mg/ml; flow rate 0.75 mL/min.; detector UV 220 nm). Anal. Calcd forC₂₆H₂₇N₃O₄S*0.7H₂O, %: C, 63.71; H, 5.84; N, 8.57. Found, %: C, 63.81;H, 5.77; N, 8.34.

Example 42(E)-N-Hydroxy-3-{3-[(4-(2-methoxyphenyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118810)

The title compound was obtained from(E)-3-(3-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6c) as white crystals, using Method D, yield 59% (on 5c). M.p.190° C. ¹H NMR (DMSO-d₈, HMDSO), δ: 2.72-3.25 (8H, m); 3.67 (3H, s);6.65 (1H, d, J=16.0 Hz); 6.76-7.12 (4H, m); 7.61 (1H, d, J=16.0 Hz);7.60-8.07 (4H, m); 9.09 (1H, br s); 10.78 (1H, s). HPLC analysis onZorbax SB C₁₈ column: impurities 2% (column size 4.6×150 mm; mobilephase acetonitrile-0.1% H₃PO₄, 50:50 10 min, 100:0 5 min; sampleconcentration 1 mg/ml; flow rate 1.5 mL/min.; detector UV 254 nm). Anal.Calcd for C₂₀H₂₃N₃O₅S, %: C, 57.54; H, 5.55; N, 10.06. Found, %: C,57.26; H, 5.46; N, 9.99.

Example 43(E)-N-Hydroxy-3-{3-[(4-(2-chlorophenyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118811)

The title compound was obtained from(E)-3-(3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (d), using Method D, yield 84% (on 5d). M.p. 183° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.76-3.32 (8H, m); 6.63 (1H, d, J=16.0 Hz);6.92-7.48 (4H, m); 7.59 (1H, d, J=16.0 Hz); 7.58-8.12 (4H, m); 9.12 (1H,br s); 10.80 (1H, s). HPLC analysis on Zorbax SB C₁₈ column: impurities2% (column size 4.6×150 mm; mobile phase acetonitrile-0.1% H₃PO₄, 50:5010 min, 100:0 5 min; sample concentration 0.5 mg/ml; flow rate 1.5mL/min; detector: UV 254 nm). Anal. Calcd for C₁₉H₂₀ClN₃O₄S, %: C,54.09; H, 4.78; N, 9.96. Found, %: C, 53.99; H, 4.73; N, 9.80.

Example 44(E)-N-Hydroxy-3-{3-[(4-(3-chlorophenyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118812)

The title compound was obtained from(E)-3-(3-{[4-(3-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6e), using Method D, yield 75% (on 5e). M.p. 201° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.83-3.45 (8H, m); 6.63 (1H, d, J=16.0 Hz);6.68-7.02 (3H, m); 7.16 (1H, t, J=7.8 Hz); 7.58 (1H, d, J=16.0 Hz);7.60-8.07 (4H, m); 9.16 (1H, br s); 10.72 (1H, s). HPLC analysis onSymmetry C₈ column: impurities 3.3% (column size 3.9×150 mm; mobilephase acetonitrile-0.1M phosphate buffer (pH 2.5), 45:55; sampleconcentration 0.5 mg/ml; flow rate 1.4 mL/min; detector UV 254 nm).Anal. Calcd for C₁₉H₂₀ClN₃O₄S, containing 4% of inorganic impurities, %:C, 51.93; H, 4.59; N, 9.56. Found, %: C, 52.00; H, 4.59; N, 9.39.

Example 45(E)-N-Hydroxy-3-{3-[(4-(2-pyridinyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide(PX118807)

The title compound was obtained from(E)-3-(3-{[4-(2-pyridinyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6f), using Method D, yield 63% (on 5f). M.p. 112° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.78-3.18 (4H, m); 3.41-3.76 (4H, m); 6.45-6.91(3H, m); 7.38-8.19 (7H, m); 9.13 (1H, br s); 10.78 (1H, br s). HPLCanalysis on Symmetry C₈ column: impurities 4% (column size 3.9×150 mm;mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 35:65; sampleconcentration 0.5 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm).Anal. Calcd for C₁₈H₂₀N₄O₄S*H₂O, containing 1.5% of inorganicimpurities, %: C, 52.39; H, 5.37; N, 13.58. Found, %: C, 52.45; H, 5.23;N, 13.39.

Example 46(E)-3-[3-({4-[4-(1-Chlorovinyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2-propenamide(PX118933)

The title compound was obtained from(E)-3-[3-({4-[4-(1-chlorovinyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6g), using Method D, yield 24% (on 5g). M.p. 203° C. (dec.).TLC: single spot at R_(f) 0.3 (ethyl acetate-methanol, 4:1;detection—UV-254 nm). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.94-3.20 (4H, m);3.21-3.63 (4H, m, overlapped with a signal of water); 5.38 (1H, d, J=4.0Hz); 5.83 (1H, d, J=4.0 Hz); 6.63 (1H, d, J=16.0 Hz); 6.93 (2H, d, J=9.0Hz); 7.54 (2H, d, J=9.0 Hz); 7.60 (1H, d, J=16.0 Hz); 7.43-8.05 (4H, m);9.16 (1H, br s); 10.85 ppm (1H, br s). Anal. Calcd for C₂₁H₂₂ClN₃O₄S,containing 1.9% of inorganic material, %: C, 55.24; H, 4.86; N, 9.20.Found, %: C, 55.22; H, 4.78; N, 9.45.

Example 47(E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2-propenamide(PX118951)

The title compound was obtained from(E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6h), using Method D, yield 17% (on 5h). M.p. 189° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.36-2.57 (8H, m, overlapped with a signal ofDMSO); 2.80 (6H, s); 2.83-2.94 (4H, m); 6.60 (2H, d, J=8.0 Hz); 6.61(1H, d, J=15.7 Hz); 6.96 (2H, d, J=8.0 Hz); 7.57 (1H, d, J=15.7 Hz);7.66-7.75 (2H, m); 7.83-7.97 (2H, m); 9.17 (1H, br s); 10.83 (1H, br s).HPLC analysis on Alltima C₁₈ column: impurities 3% (column size 4.6×150mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 15:85;sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV 220nm). Anal. Calcd for C₂₃H₃₀N₄O₄S, %: C, 60.24; H, 6.59; N, 12.22. Found,%: C, 60.05; H, 6.52; N, 12.16.

Example 48(E)-N-Hydroxy-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}-sulfonyl)phenyl]-2-propenamide(PX118934)

The title compound was obtained from(E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (61), using Method D, yield 68% (on 51). M.p. 178° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.41-2.68 (6H, m, overlapped with a signal ofDMSO); 2.75-3.00 (6H, m); 6.61 (1H, d, J=16.0 Hz); 7.34 (1H, d, J=8.4Hz); 7.39-7.52 (2H, m); 7.57 (1H, d, J=16.0 Hz); 7.63-7.97 (8H, m); 9.17(1H, br s); 10.84 ppm (1H, br s). HPLC analysis on Omnispher C₁₈ column:impurities 2.2% (column size 4.6×150 mm; mobile phase acetonitrile-0.2 Macetate buffer (pH 5.0), 40:60; sample concentration 0.5 mg/ml; flowrate 1.5 mL/min; detector UV 230 nm). Anal. Calcd for C₂₅H₂₇N₃O₅S, %: C,62.35; H, 5.65; N, 8.73. Found, %: C, 62.42; H, 5.56; N, 8.69.

Example 49(E)-N-Hydroxy-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-sulfonyl)phenyl]-2-propenamide(PX118935)

The title compound was obtained from(E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (6j), using Method D, yield 57% (on 5j). M.p. 130° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.54-2.68 (4H, m, overlapped with a signal ofDMSO); 2.76 (2H, t, J=5.0 Hz); 2.82-3.03 (4H, m); 4.12 (2H, t, J=5.3Hz); 6.60 (1H, d, J=16.0 Hz); 7.10 (1H, dd, J=8.9 and 2.0 Hz); 7.28 (1H,d, J=2.0 Hz); 7.31 (1H, t, J=7.9 Hz); 7.43 (1H, t, J=7.6 Hz); 7.55 (1H,d, J=16.0 Hz); 7.62-7.95 (7H, m); 9.19 (1H, br s); 10.82 ppm (1H, br s).HPLC analysis on Omnispher C₁₈ column: impurities 3.3% (column size4.6×150 mm; mobile phase acetonitrile-0.2 M acetate buffer (pH 5.0),40:60; sample concentration 0.25 mg/ml; flow rate 1.5 mL/min; detectorUV 230 nm). Anal. Calcd for C₂₅H₂₇N₃O₅S, containing 6% of inorganicimpurities, %: C, 58.61; H, 5.31; N, 8.20. Found, %: C, 58.63; H, 5.33;N, 8.01.

Example 50(E)-3-(3-{[4-(3,4-Dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide(PX118971)

The title compound was obtained from(E)-3-(3-{[4-(3,4-dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6k), using Method D, yield 71% (on 5k). M.p. 193° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.89-3.09 (4H, m); 3.18-3.33 (4H, m, overlappedwith a signal of water); 6.61 (1H, d, J=15.9 Hz); 6.89 (1H, dd, J=2.8and 8.4 Hz); 7.11 (1H, d, J=2.8 Hz); 7.38 (1H, d, J=8.4 Hz); 7.57 (1H,d, J=15.9 Hz); 7.66-7.82 (2H, m); 7.87-8.00 (2H, m); 9.16 (1H, s); 10.82(1H, s). HPLC analysis on Omnispher C₁₈ column: impurities 3.3% (columnsize 4.6×150 mm; mobile phase acetonitrile-0.2 M acetate buffer (pH5.0), 50:50; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min;detector UV 254 nm). Anal. Calcd for C₁₉H₁₉Cl₂N₃O₄S, %: C, 50.01; H,4.20; N, 9.21. Found, %: C, 49.94; H, 4.06; N, 9.10.

Example 51(E)-3-(3-{[4-(4-Chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide(PX118972)

The title compound was obtained from(E)-3-(3-{[4-(4-chlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenoylchloride (6l), using Method D, yield 79% (on 5l). M.p. 215° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 2.89-3.12 (4H, m); 3.12-3.27 (4H, m); 6.61 (1H, d,J=15.9 Hz); 6.91 (2H, d, J=8.9 Hz); 7.21 (2H, d, J=8.9 Hz); 7.57 (1H, d,J=15.9 Hz); 7.67-7.85 (2H, m); 7.86-8.05 (2H, m); 9.26 (1H, br s); 10.65(1H, br s). HPLC analysis on Alltima C₁₈ column: impurities <1% (columnsize 4.6×150 mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min;detector UV 254 nm). Anal. Calcd for C₁₉H₂₀ClN₃O₄S, %: C, 54.09; H,4.78; N, 9.96. Found, %: C, 54.08; H, 4.62; N, 9.90.

Example 52(E)-N-Hydroxy-3-[3-({4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenamide(PX118870)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 178° C. ¹H NMR (DMSO-d₆, TMS) δ: 2.60-3.49 (8H, m,partly overlapped with a signal of water), 3.09 (2H, d, J=6.0 Hz); 6.13(1H, dt, J=16.0 and 6.0 Hz), 6.49 (1H, d, J=16.0 Hz); 6.60 (1H, d,J=16.0 Hz); 7.16-7.56 (5H, m); 7.57-8.00 (5H, m); 9.20 (1H, br s); 10.78ppm (1H, br s). HPLC analysis on an Omnispher 5 C₁₈ column: impurities1.0% (column size: 4.6×150 mm—mobile phase: acetonitrile-0.1 M phosphatebuffer (pH 2.5), 25:75; sample concentration 0.16 mg/ml; flow rate: 1.3mL/min; detector UV 254 nm). Anal. Calcd. for C₂₂H₂₃N₃O₄S, %: C, 61.81;H, 5.89; N, 9.83. Found, % C, 61.43; H, 5.84; N, 9.65.

Example 53(E)-N-Hydroxy-3-(3-{[4-(4-methoxyphenyl)-1-piperazinyl]-sulfonyl}phenyl)-2-propenamide(PX118871)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 203° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.96-3.12 (8H,m); 3.66 (3H, s); 6.62 (1H, d, J=15.7 Hz); 6.79 (2H, d, J=9.4 Hz); 6.85(2H, d, J=9.4 Hz); 7.59 (1H, d, J=15.7 Hz); 7.62-7.70 (2H, m); 7.92-8.05(2H, m); 9.15 (1H, br s); 10.82 ppm (1H, br s). HPLC analysis on anOmnispher 5 C₁₈ column: impurities 1.3%. (column size 4.6×150 mm; mobilephase acetonitrile-0.1 M phosphate buffer (pH 2.5), 40:60; sampleconcentration 0.5 mg/ml; flow rate 1.5 mL/min; detector UV 220 nm).Anal. Calcd. for C₂₀H₂₃N₃O₅S, %: C, 57.54; H, 5.55; N, 10.06. Found, %:C, 57.55; H, 5.41; N, 9.98.

Example 54(E)-N-hydroxy-3-(3-{[4(3-methoxyphenyl)piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118872)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 196° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.96-3.10 (4H,m), 3.13-3.26 (4H, m); 3.68 (3H, s); 6.34-6.52 (3H, m); 6.61 (1H, d,J=15.7 Hz); 7.08 (1H, t, J=7.9 Hz); 7.57 (1H, d, J=15.7 Hz); 7.64-7.80(2H, m); 7.89-7.98 (2H, m); 9.15 (1H, br s); 10.81 ppm (1H, br s). HPLCanalysis on an Alltima C₁₈ column: impurities 3.5% (column size 4.6×150mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 50:50;sample concentration 0.5 mg/ml; flow rate 1.4 mL/min; detector UV 220nm). Anal. Calcd for C₂₀H₂₃N₃O₅S, containing 1.5% of inorganicimpurities, %: C, 56.68; H, 5.47; N, 9.91. Found, %: C, 56.79; H, 5.31;N, 9.81.

Example 55(E)-3-(3-{[4-(1,3-Benzodioxol-5-ylmethyl)-1-piperazinyl]sulfonyl}-phenyl)-N-hydroxy-2-propenamide(PX118873)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 172° C. ¹H NMR (DMSO-d 6, HMDSO) δ: 2.32-2.45 (4H,m), 2.82-2.97 (4H, m); 3.34 (2H, s, overlapped with a signal of water);5.94 (2H, s); 6.60 (1H, d, J=15.7 Hz); 6.67 (1H, d, J=7.9 Hz); 6.76 (1H,s); 6.78 (1H, d, J=8.3 Hz); 7.56 (1H, d, J=15.7 Hz); 7.66-7.74 (2H, m);7.83-7.96 (2H, m); 9.14 (1H, br s); 10.80 ppm (1H, br s). HPLC analysison an Omnispher 5 C₁₈ column: impurities 1.3% (column size 4.6×150 mm;mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 35:65; sampleconcentration 1.0 mg/ml; flow rate: 1.3 mL/min; detector UV 254 nm).Anal. Calcd. for C₂₁H₂₃N₃O₆S, %: C, 56.62; H, 5.20; N, 9.43. Found, %:C, 56.35; H, 5.02; N, 9.24.

Example 56(E)-3-{3-[(4-Benzyl-1-piperazinyl)sulfonyl]phenyl}-N-hydroxy-2-propenamide(PX118874)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 185° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.42 (4H, m),2.91 (4H, m); 3.45 (2H, s); 6.59 (1H, d, J=15.7 Hz); 7.15-7.31 (5H, m);7.56 (1H, d, J=15.7 Hz); 7.62-7.76 (2H, m); 7.81-7.98 (2H, m); 9.14 (1H,br s); 10.80 ppm (1H, br s). HPLC analysis on an Omnispher 5 C₁₈ column:impurities 2.3% (column size 4.6×150 mm; mobile phase acetonitrile-0.1 Mphosphate buffer (pH 2.5), 40:60; sample concentration 0.33 mg/ml; flowrate 1.3 mL/min; detector UV 220 nm). Anal Calcd. for C₂₀H₂₃N₃O₄S, %: C,59.83; H, 5.77; N, 10.47. Found, %: C, 59.67; H, 5.62; N, 10.34.

Example 57(E)-3-[3-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2-propenamide(PX118875)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.18-2.45 (4H,m), 2.78-3.09 (4H, m); 4.36 (1H, s); 6.58 (1H, d, J=16.0 Hz); 6.89-7.20(4H, m); 7.22-7.58 (5H, m); 7.60-8.05 (4H, m); 9.98 ppm (2H, br s). HPLCanalysis on an Alltima C₁₈ column: impurities 6.5% (column size 4.6×150mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 60:40;sample concentration 0.5 mg/ml; flow rate 1.5 mL/min; detector: UV 220nm). Anal Calcd. for C₂₆H₂₅F₂N₃O₄S, %: C, 60.31; H, 5.24; N, 7.54.Found, %: C, 60.13; H, 5.17; N, 7.51.

Example 58(E)-N-Hydroxy-3-(3-{[3-methyl-4-(4-methylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118876)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 186° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 0.94 (3H, d,J=6.4 Hz); 2.20 (3H, s); 2.56-2.83 (1H, m, partly overlapped with asignal of water); 2.84-3.67 (5H, m); 3.80-4.16 (1H, m); 6.45-6.78 (4H,m); 6.94-7.20 (1H, m); 7.60 (1H, d, J=16.0 Hz); 7.69-8.14 (4H, m); 9.98(2H, br s). HPLC analysis on an Alltima C₁₈ column: impurities 3.0%(column size 4.6×150 mm; mobile phase acetonitrile-0.1 M phosphatebuffer (pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate 1.0ml/min; detector UV 220 nm). Anal. Calcd. for C₂₁H₂₅N₃O₄S*0.1EtOH, %: C,60.58; H, 6.13; N, 9.90. Found, %: C, 60.46; H, 6.05; N, 9.84.

Example 59(E)-3-(3-{[4-(2-Fluorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide(PX118877)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 176° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.83-3.15 (8H,m); 6.63 (1H, d, J=16.0 Hz); 6.83-7.27 (4H, m); 7.60 (1H, d, J=16.0 Hz);7.65-8.05 (4H, m); 9.12 (1H, br s); 10.83 ppm (1H, br s). HPLC analysison Ultra JBD: impurities 1.0% (column size 4.6×150 mm; mobile phaseacetonitrile-0.1 M phosphate buffer (pH 2.5), 60:40; sampleconcentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV 230 nm). AnalCalcd. for C₁₉H₂₀FN₃O₄S, %: C, 56.29; H, 4.97; N, 10.36. Found, %: C,56.25; H, 4.89; N, 10.16.

Example 60(E)-N-Hydroxy-3-[3-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenamide(PX118878)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 173° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.94-3.25 (8H,m); 6.63 (1H, d, J=16.0 Hz); 6.98-7.29 (3H, m); 7.39 (1H, d, J=7.6 Hz);7.69 (1H, d, J=16.0 Hz); 7.60-8.09 (4H, m); 10.05 ppm (2H, br s). HPLCanalysis on Alltima C₁: impurities 5.5% (column size 4.6×150 mm; mobilephase acetonitrile-0.1 M phosphate buffer (pH 2.5), 50:50; sampleconcentration 1.0 mg/ml; flow rate 1.5 mL/min; detector UV 220 nm.)Anal. Calcd. for C₂₀H₂₀F₃N₃O₄S*0.1EtOAc, %: C, 52.78; H, 4.52; N, 9.05.Found, %: C, 52.74; H, 4.36; N, 8.88.

Example 61(E)-N-Hydroxy-3-(3-{[4-(3-nitrophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118893)

The Title Compound was Obtained Using Methods Analogous to ThoseDescribed Above. M.p. 162° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.94-3.20 (4H,m); 3.45-3.69 (4H, m); 6.65 (1H, d, J=16.0 Hz); 7.02 (2H, d, J=9.0 Hz);7.58 (1H, d, J=16.0 Hz); 7.62-7.83 (2H, m); 7.84-8.20 (4H, m); 10.20(2H, br s). HPLC analysis on Omnisphere 5 C₁₈: impurities 2.0% (columnsize 4.6×150 mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH2.5), 40:60; sample concentration 0.3 mg/ml; flow rate 1.5 mL/min;detector UV 220 nm). Anal. Calcd. for C₁₉H₂₀N₄O₆S containing 2.3%inorganic material, %: C, 51.56; H, 4.55; N, 12.66. Found, %: C, 51.54;H, 4.50; N, 12.57.

Example 62(E)-N-Hydroxy-3-(3{-[4-(2-pyrimidinyl)-1-piperazinyl]sulfonyl}-phenyl)-2-propenamide(PX118894)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 200° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.78-3.15 (4H,m); 3.63-3.94 (4H, m); 6.58 (1H, d, J=16.0 Hz); 6.63 (1H, t, J=6.4 Hz);7.56 (1H, d, J=16.0 Hz); 7.57-8.12 (4H, m); 8.34 (2H, d, J=6.4 Hz); 9.16(1H, br s); 10.80 ppm (1H, br s). HPLC analysis on Alltima C₁₈:impurities 4.8% (column size: 4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 30:70; sample concentration 1.0 mg/ml; flowrate 1.15 mL/min; detector UV 254 nm.) Anal. Calcd for C₁₇H₁₉N₅O₄S, %:C, 52.43; H, 4.92; N, 17.98. Found, %: C, 52.37; H, 4.89; N, 17.69.

Example 63(E)-3-(3-{[4-(2,2-Diphenylethyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide(PX118913)

The title compound was obtained using methods analogous to thosedescribed above.

M.p. 117° C. (decomposes). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.42-2.62 (4H, m,overlapped with a signal of DMSO); 2.70-2.87 (4H, m); 2.92 (2H, d, J=7.3Hz); 4.18 (1H t, J=7.3 Hz); 6.58 (1H, d, J=15.8 Hz); 7.02-7.35 (10H, m);7.53 (1H, d, J=15.8 Hz); 7.61-7.70 (2H, m); 7.80-7.92 (2H, m); 9.14 (1H,br s); 10.80 ppm (1H, br s). HPLC analysis on Omnisphere C₁₈: impurities4.5% (column size 4.6×150 mm; mobile phase acetonitrile-0.1 M phosphatebuffer (pH 2.5); 40:60; sample concentration 0.5 mg/ml; flow rate: 1.2mL/min; detector UV 220 nm.) Anal. Calcd. for C₂₇H₂₉N₃O₄S*0.2 M Et₂Ocontaining 1.8% of inorganic impurities, %: C, 64.75; H, 6.06; N, 8.15.Found, %: C, 64.76; H, 6.07; N, 8.19.

Example 64(E)-N-Hydroxy-3-[3-({4-[2-(2naphthyl)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenamide(PX118914)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 184° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.38-3.07(12H, m, partly overlapped with a signal of DMSO); 6.63 (1H, d, J=16.0Hz); 7.20-7.54 (4H, m); 7.57-7.98 (8H, m); 9.16 (1H, br s); 10.78 ppm(1H, br s). HPLC analysis on Alltima C₁₈: impurities 1.0% (column size4.6×150 mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5),35:65; sample concentration 1.0 mg/ml; flow rate 1.2 mL/min; detector UV220 nm). Anal. Calcd. for C₂₅H₂₇N₃O₄S, %: C, 64.50; H, 5.85; N, 9.03.Found, %: C, 64.34; H, 5.74; N, 9.02.

Example 65 3-(4-Chlorosulfonylphenyl)acrylic acid (8)

To neat chlorosulfonic acid (26.5 mL, 0.4 mol) at 18° C. temperatureslowly cinnamic acid (7) (7.35 g, 0.05 mol) was added. As the reactionproceeded, hydrogen chloride gas evolved. The reaction mixture wasstirred successively at 20° C. for 3 hours and at 42° C. for 3 hours.The dark, viscous syrup was poured into ice water, and the precipitatedsolid was filtered and washed with water. The title compound wasobtained (6.8 g, 55%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 6.55(1H, d, J=16.0 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, brs).

Example 66(E)-3-[4-({4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (9a)

To a suspension of 1-(α,α,α-trifluoro-m-tolyl)piperazine hydrochloride(0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO₃ (0.27 g, 3.24mmol) in water (4 mL) and a solution of3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) wereadded and the resultant mixture was stirred at ambient temperature for20 hours. The reaction mixture was poured into water (50 mL) and the pHof the medium was brought to ˜4 with 2 N HCl. The precipitated solid wasfiltered, washed with water, and dried in vacuum to give the titlecompound (0.59 g, 82%). ¹H NMR (DMSO-d₆, HMDSO), δ: 2.96-3.67 (8H, m,overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57(4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d,J=8.4 Hz); 12.71 (1H, br s).

Example 67(E)-3-[(4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (9b)

To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47 g, 1.62mmol) in dioxane (5 mL) a solution of NaHCO₃ (0.27 g, 3.24 mmol) inwater (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid(8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirredat ambient temperature for 20 hours. The reaction mixture was pouredinto water (50 mL), the pH of the medium was brought to ˜4 with 2 N HCl,and extracted with ethyl acetate. The extract was washed successivelywith water, brine, and dried (Na₂SO₄). The solvent was removed and thecrude product was crystallized from dioxane to give the title compound(0.58 g, 63%) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.19-2.50(4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H,s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6and 5.6 Hz); 7.72 (1H, d, J=116.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H,d, J=8.2 Hz); 12.68 (1H, br s).

Example 68(E)-3-[4-({4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10a)

To a suspension of(E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (9a) (0.30 g, 0.69 mmol) in dichloromethane (7 mL) oxalyl chloride(0.2 mL, 2.4 mmol) and a drop of dimethylformamide were added. Thereaction mixture was stirred at ambient temperature for 0.5 hours and at42° C. for 1 hour. The reaction mixture was evaporated and the residuewas dried in vacuum to give(E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10a) (0.31 g) in a form of a crude product.

Example 69(E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10b)

To a solution of(E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoicacid (b) (0.25 g, 0.5 mmol) in dichloromethane (7 mL) oxalyl chloride(0.15 mL, 1.75 mmol) and a drop of dimethylformamide were added. Thereaction mixture was stirred at ambient temperature for 1 hour, then themixture was evaporated and the residue was dried in vacuum to give(E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10b) (0.26 g) in a form of a crude product.

Example 70(E)-N-Hydroxy-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}-sulfonyl)phenyl]-2-propenamide(PX118937)

To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) intetrahydrofuran (5.0 mL) a solution of NaHCO₃ (0.40 g, 4.8 mmol) inwater (6 mL) was added and the resultant mixture was stirred at ambienttemperature for 5 minutes. The reaction mixture was added to asuspension of(E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture wasstirred at ambient temperature for 0.5 hours. The mixture was pouredinto water (25 mL), the precipitate was filtered, washed with water,ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179°C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m,overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H,d, J=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, J=7.7Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2H, d, J=8.4Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC analysis on Omnispher 5 C₁₈column: impurities 3.5% (column size 4.6×150 mm; mobile phaseacetonitrile-0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd forC₂₀H₂₀F₃N₃O₄S, %: C, 52.74; H, 4.43; N, 9.23; S, 7.04. Found, %: C,52.04; H, 4.29; N, 8.86; S, 7.20.

Example 71(E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2-propenamide(PX118965)

To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5 mmol) intetrahydrofuran (5.0 mL) a solution of NaHCO₃ (0.30 g, 3.5 mmol) inwater (5 mL) was added and the resultant mixture was stirred at ambienttemperature for 5 minutes. The reaction mixture was added to a solutionof(E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoylchloride (10b) (0.26 g) in tetrahydrofuran (5 mL) and the obtainedmixture was stirred at ambient temperature for 0.5 hours. The mixturewas poured into water (25 mL), extracted with ethyl acetate, the extractwas washed with water, brine, and dried (Na₂SO₄). The solvent wasremoved and the residue was chromatographed on silica gel withchloroform-isopropanol (9:1) as eluent to give the title compound (0.087g, 34%). M.p. 125-126° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 2.26-2.42 (4H, m);2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d, J=15.8 Hz); 7.07 (4H, t,J=8.6 Hz); 7.37 (4H, dd, J=8.4 and 5.6 Hz); 7.57 (1H, d, J=15.8 Hz);7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d, J=8.0 Hz); 9.19 (1H, s); 10.93 (1H,s). HPLC analysis on Alltima C₁₈ column: impurities 2% (column size4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),70:30; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector:UV 215 nm). Anal. Calcd for C₂₆H₂₅F₂N₃O₄S*0.3 Et₂O*0.2 iso-PrOH*0.1CHCl₃(an exhaustively dried material contains all the indicated traces ofsolvents (PMR)), %: C, 59.87; H, 5.35; N, 7.51; S, 5.73. Found, %: C,59.85; H, 5.36; N, 7.29; S, 5.60.

Example 721-(1,3-Benzodioxol-5-ylmethyl)-4-({-[(E)-3-(hydroxyamino)-3-oxo-1-propenyl]phenyl}sulfonyl)piperazin-1-iumdihydrogen phosphate (PX118882)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 210-211° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.30-2.45(4H, m, overlapped with a signal of DMSO); 2.82-2.96 (4H, m); 3.36 (2H,s); 3.89-4.67 (br s, interchangeable protons); 5.95 (2H, s); 6.62 (1H,d, J=15.8 Hz); 6.68 (1H, d, J=7.8 Hz); 6.77 (1H, s); 6.79 (1H, d, J=7.8Hz); 7.53 (2H, d, J=15.8 Hz); 7.73 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0Hz). HPLC analysis on Omnispher 5 C₁₈: impurities 2.5% (column size4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),20:80; sample concentration 0.5 mg/ml; flow rate 1.5 ml/min; detector UV220 nm). Anal. Calcd. for C₂₁H₂₃N₃O₆S*H₃PO₄*0.25 NaH₂PO₄, %: C, 43.98;H, 4.66; N, 7.33; S, 5.59. Found, %: C, 43.59; H, 4.75; N, 7.50; S,5.70.

Example 73(E)-N-Hydroxy-3-(4-{[4-(4-nitrophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118918)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 199-200° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.97-3.09(4H, m); 3.49-3.62 (4H, m); 6.61 (1H, d, J=15.7 Hz); 6.99 (2H, d, J=9.2Hz); 7.52 (1H, d, J=15.7 Hz); 7.78 (2H, d, J=9.0 Hz); 7.81 (2H, d, J=9.0Hz); 8.02 (2H, d, J=9.2 Hz); 9.17 (1H, s); 10.91 (1H, s). HPLC analysison Omnispher 5 C₁₈: impurities 3.0% (column size 4.6×150 mm; mobilephase acetonitrile-0.1M phosphate buffer (pH 2.5), 40:60; sampleconcentration 0.25 mg/ml; flow rate 1.5 mL/min; detector UV 270 nm).Anal. Calcd. for C₁₉H₂₀N₄O₆S, %: C, 52.77; H, 4.66; N, 12.96; S, 7.41.Found, %: C, 52.56; H, 4.74; N, 12.41; S, 7.28.

Example 74(E)-3-(4-{[4-(2-Fluorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide(PX118891)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 196-197° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 3.00-3.14(8H, m); 6.63 (1H, d, J=15.8 Hz); 6.92-7.18 (4H, m); 7.55 (1H, d, J=15.8Hz); 7.80 (2H, d, J=8.6 Hz); 7.84 (2H, d, J=8.6 Hz); 9.16 (1H, s); 10.92(1H, s). HPLC analysis on Alltima C₁₈: impurities 3.5% (column size4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),50:50; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV254 nm.) Anal. Calcd. for C₁₉H₂₀FN₃O₄S*0.2 EtOAc, %: C, 56.21; H, 5.15;N, 9.93; S, 7.58. Found, %: C, 56.07; H, 5.10; N, 9.97; S, 7.60.

Example 75(E)-N-Hydroxy-3-(4-{[4-(3-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118892)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 199-200° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 2.95-3.06(4H, m); 3.13-3.25 (4H, m); 3.68 (3H, s); 6.38 (1H, d, J=8.0 Hz); 6.42(1H, s); 6.47 (1H, d, J=8.2 Hz); 6.61 (1H, d, J=16.0 Hz); 7.09 (1H, t,J=8.0 Hz); 7.54 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.4 Hz); 7.83 (2H, d,J=8.4 Hz); 9.17 (1H, s); 10.91 (1H, br s). HPLC analysis on Omnispher 5C₁₈: impurities 4.5% (column size 4.6×150 mm; mobile phaseacetonitrile-0.1M phosphate buffer (pH 2.5), 45:55; sample concentration0.15 mg/ml; flow rate 1.2 mL/min; detector UV 254 nm). Anal. Calcd. forC₂₀H₂₃N₃O₅S*0.1 EtOAc*0.2H₂O, %: C, 57.00; H, 5.67; N, 9.77; S, 7.46.Found, %: C, 57.04; H, 5.52; N, 9.64; S, 7.38.

Example 76(E)-N-Hydroxy-3-(4-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide(PX118905)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 225-226° C. ₁H NMR (DMSO-d₆, HMDSO) δ: 2.89-3.13(8H, m); 3.70 (3H, s); 6.63 (1H, d, J=15.8 Hz); 6.83-7.00 (4H, m); 7.56(1H, d, J=15.8 Hz); 7.80 (2H, d, J=8.2 Hz); 7.85 (2H, d, J=8.2 Hz); 9.18(1H, br s); 10.93 (1H, br s). HPLC analysis on Omnispher 5 C₁₈:impurities 4.5%. (column size 4.6×150 mm; mobile phase acetonitrile-0.1Mphosphate buffer (pH 2.5), 40:60; sample concentration 0.2 mg/ml; flowrate 1.2 mL/min; detector UV 254 nm). Anal. Calcd. for C₂₀H₂₃N₃O₅S*0.2EtOAc*0.2H₂O, %: C, 56.95; H, 5.74; N, 9.58; S, 7.31. Found, %: C,56.95; H, 5.66; N, 9.40; S, 7.54.

Example 773-(4-[4-(3-Chloro-phenyl)-piperazine-1-sulfonyl]-phenyl)-N-hydroxy-acrylamide(PX118906)

The Title Compound was Obtained Using Methods Analogous to ThoseDescribed Above.

Example 78N-Hydroxy-3-[4-(4-pyrimidin-2-yl-piperazine-1-sulfonyl)-phenyl]-acrylamide(PX118907)

The title compound was obtained using methods analogous to thosedescribed above.

Example 793-[4-(4-Benzhydryl-piperazine-1-sulfonyl)-phenyl-N-hydroxy-acrylamide(PX118910)

The title compound was obtained using methods analogous to thosedescribed above.

Example 80N-Hydroxy-3-[4-(3-methyl-4-m-tolyl-piperazine-1-sulfonyl)-phenyl]-acrylamide(PX118911)

The title compound was obtained using methods analogous to thosedescribed above.

Method E—General Synthesis of 1-Acylpiperazines

Appropriate carboxylic acid (1-2 mmol) and hydroxybenztriazole (1 eq)were suspended in chloroform (2 ml/1 mmol) and a solution of1,3-dicylcohexylcarbodiimide (DCC) (1 eq) in a minimal amount ofdimethylformamide was added. The mixture was stirred for 30 minutes atroom temperature to give white suspension. The mixture was transferredslowly to a pre-cooled solution of anhydrous piperazine (5 eq) inchloroform (1 mL/1 mmol). The reaction was stirred for 4 hours at roomtemperature, the white suspension (DCU) was filtered, and the filtratewas extracted with 2 M HCl. The HCl extracts were basified with 2 M NaOHto pH 9, extracted with ethyl acetate, and the organic extract waswashed with brine, dried (Na₂SO₄), and evaporated under reducedpressure. The crude product was used without further purification, orwas purified on silica gel (20 g) with methanol-NH₄OH (ca. 95:5 to90:10) as eluent.

Example 81 2-Naphthyl(1-piperazinyl)methanone (13a)

The title compound was prepared from naphthalene 2-carboxylic acid (2a),using Method E, yield 94%. ¹H NMR (CDCl₃, HMDS), δ: 1.92 (s, 1H); 2.87(t, J=5.0 Hz, 4H); 3.63 (t, J=5.0 Hz, 4H); 7.43-7.74 (m, 3H); 7.89-8.12(m, 4H).

Example 82 2-(5-Methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-ethanone(13b)

The title compound was prepared from 2-(5-methoxy-1H-indol-3-yl)aceticacid (12b), using Method E, yield 75%. ¹H NMR (CDCl₃, HMDS), δ: 1.61 (s,1H); 2.63 (t, J=5.0 Hz, 2H); 2.78 (t, J=5.0 Hz, 2H); 3.45 (t, J=5.0 Hz,2H); 3.65 (t, J=5.0 Hz, 2H); 3.78 (s, 2H); 3.83 (s, 3H); 6.78 (dd, J=8.8and 3.0 Hz, 1H); 7.06 (t, J=3.0 Hz, 2H); 7.22 (d, J=8.8 Hz, 1H); 8.27(s, 1H).

Example 83 2-(2-Naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13c)

The title compound was prepared from 2-(2-naphthyloxy)acetic acid (2c),using Method E, yield 97%. ¹H NMR (CDCl₃, HMDS), δ: 1.69 (s, 1H); 2.83(t, J=5.0 Hz, 4H); 3.61 (t, J=5.0 Hz, 4H); 4.81 (s, 2H); 7.12-7.58 (m,4H); 7.69-7.92 (m, 3H).

Example 84 2-(1-Naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13d)

The title compound was prepared from 2-(1-naphthyloxy)acetic acid (d),using Method E, yield 82%. ¹H NMR (CDCl₃, HMDS), δ: 1.87 (s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.83 (t, J=5.0 Hz, 2H); 3.45 (t, J=5.0 Hz, 2H); 3.65(t, J=5.0 Hz, 2H); 3.89 (s, 2H); 7.29-7.61 (m, 3H); 7.65-7.96 (m, 4H).

Example 85 2-(1-Benzothiophen-3-yl)-1-(1-piperazinyl)-1-ethanone (13e)

The title compound was prepared from 2-(1-benzothiophen-3-yl)acetic acid(2e), using Method E, yield 92%. ¹H NMR (CDCl₃, HMDS), δ: 1.61 (s, 1H);2.67 (t, J=5.0 Hz, 2H); 2.83 (t, J=5.0 Hz, 2H); 3.43 (t, J=5.0 Hz, 2H);3.67 (t, J=5.0 Hz, 2H); 3.81 (s, 2H); 7.21-7.54 (m, 3H); 7.69-7.98 (m,2H).

Example 86 3-(1H-Indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f)

The title compound was prepared from 3-(1H-indol-3-yl)propanoic acid(12f), using Method E, yield 79%. ¹H NMR (CDCl₃, HMDS), δ: 2.03 (s, 1H);2.54-2.89 (m, 6H); 3.03-3.21 (m, 2H); 3.34 (t, J=5.0 Hz, 2H); 3.58 (t,J=5.0 Hz, 2H); 7.00-7.45 (m, 4H); 7.52-7.74 (m, 1H); 8.13 (bs, 1H).

Example 87 1H-Indol-3-yl(1-piperazinyl)methanone (13g)

The title compound was prepared from 1H-indole-3-carboxylic acid (12g),using Method E, yield 39%. ¹H NMR (CDCl₃, HMDS), δ: 1.67 (s, 1H); 2.89(t, J=5.0 Hz, 4H); 3.69 (t, J=5.0 Hz, 4H); 7.09-7.43 (m, 4H); 7.63-7.87(m, 1H); 9.27 (bs, 1H).

Example 88 Tert-butyl 4-benzoyl-1-piperazinecarboxylate (15h)

To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed bya solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL)under vigorous stirring were added. The reaction mixture was stirred atambient temperature for 4 hours, diluted with brine (20 mL), andextracted with ethyl acetate (2×25 mL). The organic extract was washedsuccessively with brine (20 mL), saturated NaHCO₃ (20 mL), saturatedKH₂PO₄ (20 mL), and dried (Na₂SO₄). The solvents were evaporated to givethe title compound (1.400 g, 90%) which was used in the next step of thesynthesis without further purification. ¹H NMR (CDCl₃, HMDS), δ: 1.41(s, 9H), 2.86 (t, J=5.0 Hz, 4H); 3.62 (t, J=5.0 Hz, 4H); 7.34 (s, 5H).

Method F—General Synthesis of Tert-Butyl 1-Piperazinecarboxylates

A solution of appropriate acid 12i-k (2.75 mmol) in anhydrousdimethylformamide (4.5 mL) was cooled in ice bath under argon andcarbonyldiimidazole (0.490 g, 3.01 mmol) was added. The mixture wasstirred for 30 minutes, then a solution of N-Boc-piperazine 14 (2.75mmol) in dimethylformamide (3 mL) was added. The mixture was stirred atice bath temperature for 1 hour, followed by 20 hours at roomtemperature, diluted with brine (20 mL), and extracted with ethylacetate (3×25 mL). The organic phase was washed successively with brine(20 mL), saturated KH₂PO₄ (20 mL), brine (20 mL), and dried (Na₂SO₄).The solvent was evaporated and the crude product was used in a furtherstep of the synthesis without additional purification, or was purifiedon silica gel (20 g) with ethyl acetate as eluent.

Example 89 tert-Butyl4-[4-(dimethylamino)benzoyl]-1-piperazinecarboxylate (15i)

The title compound was prepared from 4-(dimethylamino)benzoic acid(12i), using Method F, yield 61%. ¹H NMR (CDCl₃, HMDS), δ: 1.45 (s, 9H);2.98 (s, 6H); 3.29-3.74 (m, 8H); 6.69 (d, J=8.8 Hz, 2H); 7.36 (d, J=8.8Hz, 2H).

Example 90 tert-Butyl 4-(4-cyanobenzoyl)-1-piperazinecarboxylate (15j)

The title compound was prepared from 4-cyanobenzoic acid (12j), usingMethod F, yield 96%. ¹H NMR (CDCl₃, HMDS), δ: 1.40 (s, 9H); 2.87 (t,J=5.0 Hz, 4H); 3.63 (t, J=5.0 Hz, 4H); 6.70 (d, J=8.8 Hz, 2H); 7.12 (d,J=8.8 Hz, 2H).

Example 91 tert-Butyl4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinecarboxylate (15k)

The title compound was prepared from 2-[4-(dimethylamino)phenyl]aceticacid (12k), using Method F, yield 60%. ¹H NMR (CDCl₃, HMDS), δ: 1.43 (s,9H); 2.92 (s, 6H); 3.07-3.78 (m, 8H); 3.65 (s, 2H); 6.72 (d, J=8.8 Hz,2H); 7.14 (d, J=8.8 Hz, 2H).

Method G—General Synthesis of 1-Acylpiperazines

A solution of an appropriate N-Boc-piperazine derivative 15h-k (2.5mmol) in 1 N HCl methanol (12.5 mL) (made in situ from AcCl and MeOH)was stirred for 2 hours at ambient temperature, and then the mixture wasevaporated. To the residue, water (30 mL) was added, the mixture waswashed with diethyl ether, and the pH of the aqueous phase was broughtto 9 with 2 M NaOH. The reaction product was extracted with chloroform(3×25 mL), the organic extract was washed with brine (25 mL), and dried(Na₂SO₄). The solvent was evaporated and the crude product was used in afurther step of the synthesis without additional purification, or waspurified on silica gel (20 g) with methanol-NH₄OH (9:1) as eluent.

Example 92 Phenyl(1-piperazinyl)methanone (13h)

The title compound was prepared from tert-butyl4-benzoyl-1-piperazinecarboxylate (15h), using Method G, yield 87%. ¹HNMR (CDCl₃, HMDS), δ: 1.81 (s, 1H); 2.76 (t, J=5.0 Hz, 4H); 3.56 (bs,4H); 7.41 (s, 5H).

Example 93 [4-(Dimethylamino)phenyl](1-piperazinyl)methanone (13i)

The title compound was prepared from tert-butyl4-[4-(dimethylamino)benzoyl]-1-piperazinecarboxylate (15i), using MethodG, yield 82%. ¹H NMR (CDCl₃, HMDS), δ: 1.91 (s, 1H); 2.87 (t, J=5.0 Hz,4H); 2.98 (s, 6H); 3.63 (t, J=5.0 Hz, 4H); 6.67 (d, J=8.8 Hz, 2H); 7.34(d, J=8.8 Hz, 2H).

Example 94 4-(1-piperazinylcarbonyl)benzonitrile (13j)

The title compound was prepared from tert-butyl4-(4-cyanobenzoyl)-1-piperazinecarboxylate (15j), using Method G, yield62%. ¹H NMR (CDCl₃ HMDS), δ: 1.92 (s, 1H); 2.69-3.02 (m, 4H); 3.14-3.92(m, 4H); 7.49 (d, J=8.8 Hz, 2H); 7.72 (d, J=8.8 Hz, 2H).

Example 958-(4-{2-[4-(Dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooctanamide(13k)

The title compound was prepared from tert-butyl4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinecarboxylate (15k)using Method G, yield 80%. ¹H NMR (CDCl₃, HMDS), δ: 1.63 (s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.78 (t, J=5.0 Hz, 2H); 2.92 (s, 6H); 3.41 (t, J=5.0Hz, 2H); 3.58 (t, J=5.0 Hz, 2H); 3.65 (s, 2H); 6.99 (d, J=8.8 Hz, 2H);7.11 (d, J=8.8 Hz, 2H).

Method H—General Synthesis of N-Monosubstituted Piperazines

To a suspension of LiAlH₄ (2.5 eq) in anhydrous tetrahydrofuran (2-3mL/mmol) under argon atmosphere, a solution of appropriateN-acylpiperazine 13b,c,f,g,k (1 eq) in tetrahydrofuran (1.5 mL/1 mmol)was added, and the mixture was stirred at reflux temperature until theinitial compound disappeared (3-7 hours on average). The reactionmixture was allowed to cool to room temperature and methanol, water, and1N NaOH were carefully added. The reaction mixture was stirred for 2hours at room temperature and the mixture passed through a celite pad.The filtrate was evaporated and the residue was purified on silica gel(20 g) with methanol-NH₄OH (9:1) as eluent to give the expectedpiperazine product.

Example 96 5-Methoxy-3-[2-(1-piperazinyl)ethyl]-1H-indole (16b)

The title compound was prepared from2-(5-methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-ethanone (13b), usingMethod H, yield 38%. ¹H NMR (CDCl₃, HMDS), δ: 1.61 (s, 1H); 2.47-2.81(m, 6H); 2.87-3.09 (m, 6H); 3.85 (s, 3H); 6.85 (dd, J=8.8 and 3.0 Hz,1H); 7.05 (t, J=3.0 Hz, 2H); 7.25 (d, J=8.8 Hz, 1H); 7.83 (s, 1H).

Example 97 1-[2-(2-Naphthyloxy)ethyl]piperazine (16c)

The title compound was prepared from2-(2-naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13c), using Method H,yield 43%. ¹H NMR (CDCl₃, HMDS), δ: 1.48 (s, 1H); 2.56 (t, J=5.0 Hz,4H); 2.85 (t, J=6.0 Hz, 2H); 2.92 (t, J=5.0 Hz, 4H); 4.25 (t, J=6.0 Hz,2H); 7.05-7.58 (m, 4H); 7.65-7.89 (m, 3H).

Example 98 3-[3-(1-piperazinyl)propyl]-1H-indole (16f)

The title compound was prepared from3-(1H-indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f), using Method H,yield 74%. ¹H NMR (DMSO, HMDS), δ: 1.69 (t, J=7.0 Hz, 1H); 1.78 (t,J=7.0 Hz, 1H); 2.12-2.34 (m, 6H); 2.36-2.47 (1H, overlapped with DMSOsignal); 2.49-2.76 (m, 6H); 6.67-7.00 (m, 3H); 7.05-7.45 (m, 2H); 10.49(s, 1H).

Example 99 3-(1-piperazinylmethyl)-1H-indole (16g)

The title compound was prepared from1H-indol-3-yl(1-piperazinyl)methanone (13g) using Method H, yield 63%.¹H NMR (CDCl₃, HMDS), δ: 1.81 (s, 1H); 2.49 (t, J=5.0 Hz, 4H); 2.89 (t,J=5.0 Hz, 4H); 3.72 (s, 2H); 7.05-7.52 (m, 4H); 7.65-7.83 (m, 1H); 8.14(bs, 1H).

Example 100 N,N-Dimethyl-4-[2-(1-piperazinyl)ethyl]aniline (16k)

The title compound was prepared from8-(4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooctanamide(13k), using Method H, yield 82%. ¹H NMR (CDCl₃, HMDS), δ: 1.74 (s, 1H);2.34-2.72 (m, 8H); 2.89 (s, 6H); 2.81-3.03 (m, 4H); 6.72 (d, J=8.8 Hz,2H); 7.09 (d, J=8.8 Hz, 2H).

Method J—General Synthesis of Amidoesters

A solution of dicarbonic acid monoethyl (or monomethyl) ester 18a or 18b(2.73 mmol) in anhydrous tetrahydrofuran (5 mL) under argon atmospherewas cooled in an ice bath and to the solution carbonyldiimidazole (0.500g, 3.08 mmol) was added. The mixture was stirred for 1 hour at ice bathtemperature, then appropriate piperazine (2.73 mmol) was added. Thereaction mixture was stirred at room temperature for 20 hours,concentrated under vacuum, and partitioned between brine (30 mL) andethyl acetate (40 mL). The organic layer was washed successively withwater (25 mL), 5% citric acid (25 mL), brine (25 mL), and dried (MgSO₄).The solvent was evaporated and the residue was chromatographed on silicagel (20 g) with petroleum ether-ethyl acetate as eluent affording thecorresponding reaction product.

Example 101 8-Oxo-8-(4-phenyl-piperazin-1-yl)-octanoic acid methyl ester(19a)

The title compound was obtained from suberic acid monomethyl ester (18b)and N-phenylpiperazine (17a) (commercially available) using Method J,yield 88%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.05-1.72 (m, 8H); 2.02-2.30 (m,8H); 3.30-3.60 (m, 4H); 3.51 (s, 3H); 7.21-7.51 (m, 5H).

Example 102 Ethyl 7-(4-benzhydryl-1-piperazinyl)-7-oxoheptanoate (19b)

The title compound was obtained from pimelic acid monoethyl ester (18a)and 1-(diphenylmethyl)piperazine (17b) (commercially available) usingMethod J, yield 80%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.04-1.62 (m, 9H);2.12-2.36 (m, 8H); 3.35-3.50 (m, 4H); 4.17 (q, 2H, J=7.3 Hz); 4.31 (s,1H); 7.02-7.59 (m, 10H).

Example 103 Ethyl 7-oxo-7-(4-phenyl-1-piperazinyl)heptanoate (19c)

The title compound was obtained from pimelic acid monoethyl ester (18a)and N-phenylpiperazine (17a) (commercially available) using Method J,yield 88%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.12-1.62 (m, 9H); 1.97-2.35 (m,8H); 3.27-3.59 (m, 4H); 4.17 (q, 2H, J=7.2 Hz); 7.03-7.51 (m, 5H).

Example 104 Methyl 8-(4-benzhydryl-1-piperazinyl)-8-oxooctanoate (19d)

The title compound was obtained from suberic acid monomethyl ester (b)and 1-(diphenylmethyl)piperazine (17b) (commercially available) usingMethod J, yield 91%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.02-1.67 (m, 8H);2.09-2.38 (m, 8H); 3.33-3.51 (m, 4H); 3.56 (s, 3H); 4.29 (s, 1H);7.09-7.56 (m, 10H).

Example 105 Methyl 8-[4-(2-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate(19e)

The title compound was obtained from suberic acid monomethyl ester (18b)and 1-(2-methoxyphenyl)piperazine hydrochloride (17c) (commerciallyavailable) (before the addition of hydrochloride (17c), triethylamine(3.0 mmol) was added to the reaction mixture), using Method J, yield87%. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.12-1.60 (m, 8H); 1.97-2.82 (m, 8H,overlapped with a signal of DMSO); 3.40-3.62 (m, 7H); 3.75 (s, 3H);6.92-7.15 (m, 4H).

Method K—General Synthesis of Amidoesters

To a solution of dicarbonic acid monoethyl (or monomethyl) ester 18a or18b (2.75 mmol) in anhydrous dichloromethane (10 mL) oxalyl chloride(0.84 mL, 9.63 mmol) and a drop of dimethylformamide were added, and theresulting mixture was stirred for 30 minutes at room temperaturefollowed by 1 hour at 40° C. The solution was carefully evaporated underreduced pressure and the residue was dried in vacuum at 40° C. Theresulting chloride was dissolved in anhydrous tetrahydrofuran (3 mL) andthe obtained solution to a cold suspension (ice bath) of piperazine(2.75 mmol), tetrahydrofuran (10 mL), and saturated NaHCO₃ (10 mL) undervigorous stirring was added. The stirring was continued for 1 hour atice bath temperature and 20 hours at room temperature. The mixture wasdiluted with brine (30 mL) and extracted with ethyl acetate (3×25 mL).The organic phase was washed with brine and dried (Na₂SO₄). The solventwas evaporated and the residue was chromatographed on silica gel (20 g)with benzene-ethyl acetate as eluent to give the corresponding reactionproduct.

Example 106 Ethyl 8-[4-(2-chlorophenyl)-1-piperazinyl]-8-oxooctanoate(19f)

The title compound was obtained from suberic acid monoethyl ester (18c)and 1-(2-chlorophenyl)piperazine (17d) (commercially available) usingMethod K, yield 80%. ¹H NMR (CDCl₃, HMDSO), δ: 1.13 (t, J=7.0 Hz, 3H);1.18-1.91 (m, 8H); 2.29 (t, J=6.0 Hz, 2H); 2.38 (t, J=6.0 Hz, 2H); 3.02(t, J=5.0 Hz, 4H); 3.50-3.90 (m, 4H); 4.11 (q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H); 7.14-7.48 (m, 2H).

Example 107 Ethyl 8-[4-(3-chlorophenyl)-1-piperazinyl]-8-oxooctanoate(19g)

The title compound was obtained from suberic acid monoethyl ester (8c)and 1-(3-chlorophenyl)piperazine (17e) (commercially available) usingMethod K, yield 88%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.18-1.79 (m, 8H); 2.29 (t, J=6.0 Hz, 2H); 2.36 (t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H); 3.44-3.87 (m, 4H); 4.11 (q, J=7.0 Hz, 2H); 6.66-6.92(m, 2H); 7.05-7.37 (m, 2H).

Example 108 Ethyl 7-[4-(2-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate(19h)

The title compound was obtained from pimelic acid monoethyl ester (18a)and 1-(2-chlorophenyl)piperazine (17d) (commercially available) usingMethod K, yield 79%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.18-1.89 (m, 6H); 2.29 (t, J=6.0 Hz, 2H); 2.38 (t, J=6.0 Hz, 2H); 3.00(t, J=5.0 Hz, 4H); 3.49-3.89 (m, 4H); 4.12 (q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H); 7.14-7.48 (m, 2H).

Example 109 Ethyl 7-[4-(3-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate(19i)

The title compound was obtained from pimelic acid monoethyl ester (18a)and 1-(3-chlorophenyl)piperazine (17e) (commercially available) usingMethod K, yield 78%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.18-1.89 (m, 6H); 2.29 (t, J=6.0 Hz, 2H); 2.36 (t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H); 3.45-3.89 (m, 4H); 4.12 (q, J=7.0 Hz, 2H); 6.67-6.94(m, 2H); 7.05-7.38 (m, 2H).

Method L—General Synthesis of Amidoesters

A solution of dicarbonic acid monomethyl (or monoethyl) ester 18a-c(2.75 mmol) in anhydrous dimethylformamide (3 mL) was cooled in ice bathunder argon atmosphere and carbonyldiimidazole (490 mg, 3.01 mmol) wasadded. The mixture was stirred at ice bath temperature for 30 minutesand a solution of appropriate piperazine (2.75 mmol) indimethylformamide (3 mL) was added (if the piperazine was used in ahydrochloride form triethylamine (1.0 mL) before the piperazinehydrochloride to the reaction mixture was added). The mixture wasstirred at ice bath temperature for 1 hour followed by 20 hours at roomtemperature. Then the reaction mixture was diluted with brine (50 mL)and extracted with ethyl acetate (3×25 mL). The organic phase was washedwith brine, dried (Na₂SO₄), and the solvent was evaporated. The residuewas chromatographed on silica gel with appropriate eluent to give thecorresponding reaction product.

Example 110 Ethyl 8-[4-(2-naphthoyl)-1-piperazinyl]-8-oxooctanoate (19j)

The title compound was obtained from suberic acid monoethyl ester (18c)and 2-naphthyl(1-piperazinyl)methanone (3a) using Method L, yield 79%.¹H NMR (CDCl₃, HMDSO), δ: 1.16 (t, J=7.0 Hz, 3H); 1.18-1.65 (m, 8H);2.25 (t, J=6.0 Hz, 2H); 2.38 (t, J=6.0 Hz, 2H); 3.36-3.65 (m, 8H); 4.02(q, J=7.0 Hz, 2H); 7.43-7.74 (m, 3H); 7.89-8.12 (m, 4H).

Example 111 Ethyl 8-(4-benzoyl-1-piperazinyl)-8-oxooctanoate (19k)

The title compound was obtained from suberic acid monoethyl ester (18c)and phenyl(1-piperazinyl)methanone (13h) using Method L, yield 89%. ¹HNMR (CDCl₃, HMDSO), δ: 1.28 (t, J=7.0 Hz, 3H); 1.14-1.83 (m, 8H); 2.16(t, J=7.0 Hz, 2H); 2.23 (t, J=7.0 Hz, 2H); 3.00-3.25 (m, 4H); 3.49-3.83(m, 4H); 3.98 (q, J=7.0 Hz, 2H); 7.39 (s, 5H).

Example 112 Ethyl8-{4-[4-(dimethylamino)benzoyl]-1-piperazinyl}-8-oxooctanoate (19l)

The title compound was obtained from suberic acid monoethyl ester (1c)and [4-(dimethylamino)phenyl](1-piperazinyl)methanone (31) using MethodL, yield 81%. ¹H NMR (CDCl₃, HMDSO), δ: 1.27 (t, J=7.0 Hz, 3H);1.15-1.88 (m, 8H); 2.34 (t, J=7.0 Hz, 2H); 2.52 (t, J=6.0 Hz, 2H); 2.88(s, 6H); 3.00-3.21 (m, 4H); 3.49-3.87 (m, 4H); 4.11 (q, J=7.0 Hz, 2H);7.08 (d, J=8.8 Hz, 2H); 7.35 (s, 5H).

Example 113 Ethyl 8-[4-(4-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate(19m)

The title compound was obtained from suberic acid monoethyl ester (18c)and 1-(4-methoxyphenyl)piperazine (17f) (commercially available) usingMethod L, yield 76%. ¹H NMR (CDCl₃, HMDSO), δ: 1.16 (t, J=7.0 Hz, 3H);1.05-1.76 (m, 8H); 2.22 (t, J=7.0 Hz, 2H); 2.29 (t, J=7.0 Hz, 2H);2.85-3.07 (m, 4H); 3.43-3.78 (m, 4H); 3.72 (s, 3H); 4.05 (q, J=7.0 Hz,2H); 6.83 (s, 4H).

Example 114 Ethyl 8-[4-(3-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate(19n)

The title compound was obtained from suberic acid monoethyl ester (18c)and 1-(3-methoxyphenyl)piperazine (17g) (commercially available) usingMethod L, yield 62%. ¹H NMR (CDCl₃, HMDSO), δ: 1.29 (t, J=7.0 Hz, 3H);1.16-1.85 (m, 8H); 2.16 (t, J=7.0 Hz, 2H); 2.22 (t, J=7.0 Hz, 2H);3.00-3.25 (m, 4H); 3.49-3.83 (m, 4H); 3.65 (s, 3H); 3.98 (q, J=7.0 Hz,2H); 6.36-6.67 (m, 3H); 7.05-7.23 (m, 1H).

Example 115 Ethyl 8-[4-(4-nitrophenyl)-1-piperazinyl]-8-oxooctanoate(19o)

The title compound was obtained from suberic acid monoethyl ester (18c)and 1-(4-nitrophenyl)piperazine (17h) (commercially available) usingMethod L, yield 67%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.07-1.89 (m, 8H); 2.29 (t, J=7.0 Hz, 2H); 2.36 (t, J=7.0 Hz, 2H);3.25-3.92 (m, 8H); 4.12 (q, J=7.0 Hz, 2H); 6.83 (d, J=8.8 Hz, 2H); 8.14(d, J=8.8 Hz, 2H).

Example 116 Methyl8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate(19p)

The title compound was obtained from suberic acid monomethyl ester (18b)and 2-(5-methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-ethanone (13b) usingMethod L, yield 76%. ¹H NMR (CDCl₃, HMDSO), δ: 1.12-1.89 (m, 8H); 2.29(t, J=7.0 Hz, 4H); 3.09-3.74 (m, 8H); 3.65 (s, 3H); 3.83 (s, 2H); 3.85(s, 3H); 6.89 (dd, J=8.8 and 3.0 Hz, 1H); 7.07 (t, J=3.0 Hz, 2H);7.16-7.35 (m, 1H); 8.31 (bs, 1H).

Example 117 Methyl8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-8-oxooctanoate (19r)

The title compound was obtained from suberic acid monomethyl ester (18b)and 1-[2-(2-naphthyloxy)ethyl]piperazine (16c) using Method L, yield56%. ¹H NMR (CDCl₃, HMDSO), δ: 1.14-1.81 (m, 8H); 2.29 (t, J=7.0 Hz,4H); 2.43-2.69 (m, 4H); 2.87 (t, J=5.0 Hz, 2H); 3.32-3.74 (m, 4H); 3.63(s, 3H); 4.23 (t, J=5.0 Hz, 2H); 7.03-7.23 (m, 2H); 7.29-7.52 (m, 2H);7.61-7.83 (m, 2H).

Example 118 Ethyl8-{4-[2-(1-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanoate (19s)

The title compound was obtained from suberic acid monoethyl ester (18c)and 2-(1-naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13d) using Method L,yield 65%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H); 1.18-1.85(m, 8H); 2.27 (t, J=7.0 Hz, 4H); 3.10-3.81 (m, 8H); 3.92 (s, 2H); 4.12(q, J=7.0 Hz, 2H); 7.32-7.59 (m, 3H); 7.65-7.94 (m, 4H).

Example 119 Methyl8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1-piperazinyl}-8-oxooctanoate(19t)

The title compound was obtained from suberic acid monomethyl ester (18b)and 5-methoxy-3-[2-(1-piperazinyl)ethyl]-1H-indole (16b) using Method L,yield 89%. ¹H NMR (CDCl₃, HMDSO), δ: 1.18-1.78 (m, 8H); 2.34 (t, J=7.0Hz, 4H); 2.52 (t, J=6.0 Hz, 4H); 2.65-2.89 (m, 4H); 3.38-3.74 (m, 4H);3.67 (s, 3H); 3.85 (s, 3H); 6.87 (dd, J=8.8 and 3.0 Hz, 1H); 7.03 (t,J=3.0 Hz, 2H); 7.25 (d, J=8.8 Hz, 1H); 8.01 (s, 1H).

Example 120 Ethyl8-{4-[2-(1-benzothiophen-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate(19u)

The title compound was obtained from suberic acid monoethyl ester (18c)and 2-(1-benzothiophen-3-yl)-1-(1-piperazinyl)-1-ethanone (13e) usingMethod L, yield 83%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.16-1.87 (m, 8H); 2.29 (t, J=7.0 Hz, 4H); 3.27-3.83 (m, 8H); 3.94 (s,2H); 4.12 (q, J=7.0 Hz, 2H); 7.18-7.52 (m, 2H); 7.72-7.96 (m, 2H).

Example 121 Ethyl7-[4-(3,4-dichlorophenyl)-1-piperazinyl]-7-oxoheptanoate (19y)

The title compound was obtained from pimelic acid monoethyl ester (8a)and 1-(3,4-dichlorophenyl)piperazine (17) (commercially available) usingMethod L, yield 73%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.14-1.87 (m, 6H); 2.16-2.49 (m, 4H); 2.98-3.23 (m, 4H); 3.47-3.83 (m,4H); 4.09 (q, J=7.0 Hz, 2H); 6.74 (dd, J=8.8 and 3.0 Hz, 1H); 6.96 (d,J=3.0 Hz, 1H); 7.32 (d, J=8.8 Hz, 1H).

Example 122 Ethyl 7-[4-(4-fluorophenyl)-1-piperazinyl]-7-oxoheptanoate(19v)

The title compound was obtained from pimelic acid monoethyl ester (18a)and 1-(4-fluorophenyl)piperazine (17j) (commercially available) usingMethod L, yield 74%. ¹H NMR (CDCl₃, HMDSO), δ: 1.22 (t, J=7.0 Hz, 3H);1.16-1.89 (m, 6H); 2.16-2.49 (m, 4H); 2.93-3.18 (m, 4H); 3.49-3.87 (m,4H); 4.09 (q, J=7.0 Hz, 2H); 6.77-7.14 (m, 4H).

Example 123 Ethyl 7-[4-(4-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate(19w)

The title compound was obtained from pimelic acid monoethyl ester (18a)and 1-(4-chlorophenyl)piperazine (17k) (commercially available) usingMethod L, yield 75%. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.16-1.87 (m, 6H); 2.16-2.49 (m, 4H); 3.00-3.21 (m, 4H); 3.49-3.87 (m,4H); 4.11 (q, J=7.0 Hz, 2H); 6.85 (d, J=8.8 Hz, 2H); 7.23 (d, J=8.8 Hz,2H).

Method M—Synthesis of O-Benzylhydroxamate Esters

To a solution of dicarbonic acid monoethyl (or monomethyl) ester 18a-c(2.75 mmol) in anhydrous dichloromethane (10 mL) oxalyl chloride (0.84mL, 9.63 mmol) and a drop of dimethylformamide were added, and theresulting mixture was stirred for 30 minutes at room temperaturefollowed by 1 hour at 40° C. The solution was carefully evaporated underreduced pressure and the residue was dried in vacuum at 40° C. Theresulting chloride was dissolved in anhydrous tetrahydrofuran (3 mL) andthe obtained solution to a cold suspension (ice bath) ofbenzylhydroxylamine hydrochloride (2.75 mmol), tetrahydrofuran (10 mL),and saturated NaHCO₃ (10 mL) was added under vigorous stirring. Thestirring was continued for 1 hour at ice bath temperature and 20 hoursat room temperature. The mixture was diluted with brine (30 mL) andextracted with ethyl acetate (3×25 mL). The organic phase was washedwith brine and dried (Na₂SO₄). The solvent was evaporated and theresidue was chromatographed on silica gel (20 g) with chloroform-ethylacetate (gradient from 100:0 to 50:50) as eluent to give thecorresponding reaction product (20a-c) in 80-90% yield.

Example 124 Ethyl 7-[(benzyloxy)amino]-7-oxoheptanoate (20a)

The title product was obtained from heptanedioic acid monoethyl ester,using Method M. ¹H NMR (CDCl₃, HMDSO), δ: 1.22 (t, J=7.0 Hz, 3H);1.07-1.88 (m, 6H); 1.89-2.26 (m, 2H); 2.29 (t, J=7.0 Hz, 2H); 4.11 (q,J=7.0 Hz, 2H); 4.88 (s, 2H); 7.31 (s, 5H).

Example 125 Methyl 8-[(benzyloxy)amino]-8-oxooctanoate (20b)

The title product was obtained from octanedioic acid monomethyl ester,using Method M. ¹H NMR (CDCl₃, HMDSO), δ: 1.09-1.83 (m, 8H); 1.87-2.27(m, 2H); 2.27 (t, J=7.0 Hz, 2H); 3.63 (s, 3H); 4.87 (s, 2H); 7.29 (s,5H).

Example 126 Ethyl 8-[(benzyloxy)amino]-8-oxooctanoate (20c)

The title product was obtained from octanedioic acid monoethyl ester,using Method M. ¹H NMR (CDCl₃, HMDSO), δ: 1.23 (t, J=7.0 Hz, 3H);1.09-1.83 (m, 8H); 1.87-2.27 (m, 2H); 2.27 (t, J=7.0 Hz, 2H); 4.12 (q,J=7.0 Hz, 2H); 4.87 (s, 2H); 7.29 (s, 5H).

Method N—Synthesis of O-Benzylhydroxamate Carboxylic Acids

To a solution of appropriate ester 20a-c (1, 5-2 mmol) intetrahydrofuran (5 mL), a saturated aqueous solution of LiOH (5 mL) wasadded. The mixture was stirred for 5 hours at room temperature. Theorganic volatiles were evaporated under reduced pressure and the mixturewas supplemented with water (20 mL). The mixture was washed with diethylether and aqueous phase was acidified with 2 M HCl to pH 3. The crudeproduct was extracted with ethyl acetate (3×20 mL). The organic layerwas washed with brine (3×10 mL) and dried (Na₂SO₄). The solvent wasevaporated and the residue was dried in vacuum to give expected product21a or 21b in 60-70% yield.

Example 127 7-[(Benzyloxy)amino]-7-oxoheptanoic acid (21a)

The title product was obtained from ethyl7-[(benzyloxy)amino]-7-oxoheptanoate (20a), using Method N. ¹H NMR(CDCl₃, HMDSO), δ: 1.07-1.88 (m, 6H); 1.89-2.26 (m, 2H); 2.29 (t, J=7.0Hz, 2H); 4.88 (s, 2H); 7.32 (s, 5H).

Example 128 8-[(Benzyloxy)amino]-8-oxooctanoic acid (21b)

The title product was obtained from methyl8-[(benzyloxy)amino]-8-oxooctanoate (20b) or ethyl8-[(benzyloxy)amino]-8-oxooctanoate (20c), using Method N. ¹H NMR(CDCl₃, HMDSO), δ: 1.09-1.81 (m, 8H); 1.88-2.29 (m, 2H); 2.27 (t, J=7.0Hz, 2H); 4.86 (s, 2H); 7.30 (s, 5H).

Method P—General Synthesis of O-Benzyl Hydroxamates

A solution of dicarbonic acid N-benzyloxy monoamide 21a or 21b (1 eq) inanhydrous dimethylformamide (2 mL/mmol) was cooled in ice bath underargon atmosphere, and carbonyldiimidazole (1.1 eq.) was added. Themixture was stirred at ice bath temperature for 30 minutes and asolution of appropriate piperazine (1 eq) in dimethylformamide (2mL/mmol) was added (if the piperazine was used in a hydrochloride form,triethylamine (3 eq) was added to the reaction mixture prior to thepiperazine hydrochloride). The mixture was stirred at ice bathtemperature for 1 hour followed by 20 hours at room temperature. Thenthe reaction mixture was diluted with brine and extracted with ethylacetate. The organic phase was washed with brine, dried (Na₂SO₄), andthe solvent was evaporated. The residue was chromatographed on silicagel with appropriate eluent (chloroform-ethyl acetate for less polar andethyl acetate-methanol for more polar compounds) to give thecorresponding reaction product 22a-k.

Example 129N-(Benzyloxy)-8-[4-(4-cyanobenzoyl)-1-piperazinyl]-8-oxooctanamide (22a)

The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoicacid (21b) and 4-(1-piperazinylcarbonyl)benzonitrile (13j), using MethodP, yield 79%. ¹H NMR (CDCl₃, HMDSO), δ: 1.09-1.81 (m, 8H); 1.87-2.17 (m,2H); 2.18-2.42 (m, 2H); 3.32-3.69 (m, 8H); 4.89 (s, 2H); 7.38 (s, 5H);7.52 (d, J=8.8 Hz, 2H); 7.76 (d, J=8.8 Hz, 2H); 8.03 (s, 1H).

Example 130N-(Benzyloxy)-7-oxo-7-[4-(2-pyridinyl)-1-piperazinyl]heptanamide (22b)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 1-(2-pyridinyl)piperazine (17l) (commercially available),using Method P, yield 50%. ¹H NMR (CDCl₃, HMDSO), δ: 1.16-1.81 (m, 6H);2.36 (t, J=7.0 Hz, 2H); 3.21 (q, J=6.0 Hz, 2H); 3.36-3.85 (m, 8H); 4.76(bs, 1H); 5.09 (s, 2H); 6.58-6.74 (m, 2H); 7.34 (s, 5H); 7.41-7.63 (m,1H); 8.12-8.29 (m, 1H).

Example 131N-(Benzyloxy)-8-(4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinyl)-8-oxooctanamide(22c)

The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoicacid (21b) and 2-[4-(dimethylamino)phenyl]-1-(1-piperazinyl)-1-ethanone(13k), using Method P, yield 68%. ¹H NMR (CDCl₃, HMDSO), δ: 1.05-1.81(m, 8H); 1.85-2.32 (m, 4H); 2.89 (s, 6H); 3.07-3.69 (m, 8H); 3.65 (s,2H); 4.87 (s, 2H); 6.67 (d, J=8.8 Hz, 2H); 7.07 (d, J=8.8 Hz, 2H); 7.36(s, 5H); 8.00 (s, 1H).

Example 132N-(Benzyloxy)-8-oxo-8-[4-(2-pyrimidinyl)-1-piperazinyl]octanamide (22d)

The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoicacid (2b) and 2-(1-piperazinyl)pyrimidine (17m) (commerciallyavailable), using Method P, yield 64%. ¹H NMR (CDCl₃, HMDSO), δ:1.14-1.81 (m, 8H); 1.96-2.25 (m, 2H); 2.36 (t, J=7.0 Hz, 2H); 3.43-3.94(m, 8H); 4.89 (s, 2H); 6.54 (t, J=5.0 Hz, 1H); 7.38 (s, 5H); 7.92-8.03(m, 1H); 8.32 (d, J=5.0 Hz, 2H).

Example 133N-(Benzyloxy)-8-(4-{3-[3-(dimethylamino)phenyl]propyl}-1-piperazinyl)-8-oxooctanamide(22e)

The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoicacid (21b) and N,N-dimethyl-3-[3-(1-piperazinyl)propyl]aniline (16k),using Method P, yield 63%. ¹H NMR (CDCl₃, HMDSO), δ: 1.18-1.83 (m, 8H);2.07-2.38 (m, 4H); 2.43-2.76 (m, 8H); 2.92 (s, 6H); 3.38-3.80 (m, 4H);4.92 (s, 2H); 6.71 (d, J=8.8 Hz, 2H); 7.12 (d, J=8.8 Hz, 2H); 7.41 (s,5H); 8.07-8.36 (m, 1H).

Example 134N-(Benzyloxy)-8-{4-[2-(2-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide(22f)

The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoicacid (21b) and 2-(2-naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13c),using Method P, yield 66%. ¹H NMR (CDCl₃, HMDSO), δ: 1.14-1.76 (m, 8H);1.94-2.40 (m, 4H); 3.29-3.74 (m, 8H); 4.83 (s, 2H); 4.88 (s, 2H);7.07-7.30 (m, 3H); 7.36 (s, 5H); 7.31-7.58 (m, 1H); 7.65-7.92 (m, 3H);8.25 (bs, 1H).

Example 135N-(Benzyloxy)-7-{4-[3-(1H-indol-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptanamide(22g)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 3-(1H-indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f),using Method P, yield 63%. ¹H NMR (CDCl₃, HMDSO), δ: 1.09-1.85 (m, 6H);1.92-2.41 (m, 4H); 2.58-3.00 (m, 4H); 3.05-3.72 (m, 8H); 4.89 (s, 2H);6.91-7.39 (m, 5H); 7.38 (s, 5H); 7.52-7.74 (m, 1H); 8.25-8.76 (m, 1H).

Example 136N-(Benzyloxy)-7-[4-(1H-indol-3-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide(22h)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 1H-indol-3-yl(1-piperazinyl)methanone (13g), using MethodP, yield 69%. ¹H NMR (CDCl₃, HMDSO), δ: 1.14-1.78 (m, 6H); 1.87-2.45 (m,4H); 3.34-3.78 (m, 8H); 4.87 (s, 2H); 7.14-7.54 (m, 5H); 7.41 (s, 5H);7.58-7.83 (m, 1H); 9.14-9.38 (m, 1H).

Example 137N-(Benzyloxy)-7-{4-[3-(1H-indol-3-yl)propyl]-1-piperazinyl}-7-oxoheptanamide(22i)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 3-[3-(1-piperazinyl)propyl]-1H-indole (16f), using MethodP, yield 87%. ¹H NMR (CDCl₃, HMDSO), δ: 1.14-2.00 (m, 8H); 2.12-2.56 (m,8H); 2.67-2.96 (m, 4H); 3.32-3.71 (m, 4H); 4.89 (s, 2H); 6.92-7.36 (m,5H); 7.38 (s, 5H); 7.49-7.69 (m, 1H); 7.85-8.00 (m, 1H).

Example 138N-(Benzyloxy)-7-[4-(H-indol-3-ylmethyl)-1-piperazinyl]-7-oxoheptanamide(22j)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 3-(1-piperazinylmethyl)-1H-indole (16g), using Method P,yield 59%. ¹H NMR (CDCl₃, HMDSO), δ: 1.16-1.87 (m, 6H); 2.03-2.60 (m,8H); 3.32-3.69 (m, 4H); 3.72 (s, 2H); 4.89 (s, 2H); 7.05-7.34 (m, 5H);7.38 (s, 5H); 7.60-7.85 (m, 1H); 8.03-8.41 (m, 1H).

Example 139N-(Benzyloxy)-7-[4-(3,4-dimethylphenyl)-1-piperazinyl]-7-oxoheptanamide(22k)

The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoicacid (21a) and 1-(3,4-dimethylphenyl)piperazine (17n) (commerciallyavailable), using Method P, yield 71%. ¹H NMR (CDCl₃, HMDSO), δ:1.14-1.80 (m, 6H); 2.11 (s, 3H) 2.16 (s, 3H); 2.36-2.49 (m, 4H);3.36-3.85 (m, 8H); 4.89 (s, 2H); 6.70 (dd, J=8.8 and 3.0 Hz, 1H); 6.86(d, J=3.0 Hz, 1H); 7.02 (d, J=8.8 Hz, 1H), 7.34 (s, 5H).

Method Q—General Synthesis of Hydroxamic Acids from Amidoesters

To a 1 M solution of hydroxylamine hydrochloride in methanol (5 mL, 5mmol) a 5 M solution of sodium methylate (1 mL, 5 mmol) was added, andthe precipitate was filtered off. To the filtrate, a solution ofappropriate amidoester (19a-e) (2.47 mmol) in methanol (3 mL) was addedand the resultant mixture was stirred at room temperature for 24 hours.The mixture was acidified with acetic acid to pH 5 and the solvent wasevaporated. The residue was extracted with ethyl acetate (50 mL), theextract was washed with water, brine, and dried (MgSO₄). The extract wasfiltrated, concentrated to ca. 5-10 mL, and allowed to crystallize. Theprecipitate was filtered, washed with ethyl acetate, and dried in vacuumto give the corresponding hydroxamic acid.

Example 140 8-Oxo-8-(4-phenyl-piperazin-1-yl)-octanoic acid hydroxyamide(PX117402)

The title compound was obtained from8-oxo-8-(4-phenyl-piperazin-1-yl)-octanoic acid methyl ester (19a) byMethod Q, yield 42%. M.p. 134-136° C. ¹H NMR (DMSO-d₆, HMDSO), δ:1.16-1.38 (m, 4H); 1.38-1.60 (m, 4H); 1.93 (t, 2H, J=7.4 Hz); 2.33 (t,2H, J=7.2 Hz); 3.09 (m, 4H); 3.57 (m, 4H); 6.80 (t, 1H, J=7.1 Hz); 6.94(d, 2H, J=8.0 Hz); 7.22 (t, 2H, J=7.7 Hz); 8.66 (s, 1H); 10.33 (s, 1H).HPLC analysis on Symmetry C₈ column: impurities 1.3% (column size3.9×150 mm; mobile phase acetonitrile-0.1% H₃PO₄, 30:70; detector UV 220nm; sample concentration 0.5 mg/ml; flow rate 1.1 mL/min). Anal. Calcdfor C₁₈H₂₇N₃O₃, %: C, 64.84; H, 8.16; N, 12.60. Found, %: C, 64.71; H,8.20; N, 12.52.

Example 141 7-(4-Benzhydryl-piperazin-1-yl)-7-oxo-heptanoic acidhydroxyamide (PX117403)

The title compound was obtained from ethyl7-(4-benzhydryl-1-piperazinyl)-7-oxoheptanoate (19b) by Method Q, yield29%. M.p. 157-159° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.08-1.32 (m, 2H);1.35-1.60 (m, 4H); 1.82-2.02 (m, 2H); 2.03-2.40 (m, 6H); 3.23-3.60 (m,4H overlapped with a water signal of DMSO); 4.30 (s, 1H); 7.09-7.52 (m,10H); 8.68 (s, 1H); 10.34 (s, 1H). HPLC analysis on Zorbax Rx-C₁₈column: impurities 1.5% (column size 4.6×150 mm; mobile phaseacetonitrile-water, 80:20; detector UV 220 nm; sample concentration 1.0mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C₂₄H₃₁N₃O₃, %: C, 70.39;H, 7.63; N, 10.26. Found, %: C, 70.09; H, 7.67; N, 10.11.

Example 142 7-Oxo-7-(4-phenyl-piperazin-1-yl)-heptanoic acidhydroxyamide (PX117404)

The title compound was obtained from ethyl7-oxo-7-(4-phenyl-1-piperazinyl)heptanoate (19c) by Method Q, yield 27%.M.p. 107-109° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.15-1.36 (m, 2H); 1.38-1.60(m, 4H); 1.93 (t, 2H, J=7.1 Hz); 2.33 (t, 2H, J=7.3 Hz); 3.09 (m, 4H);3.58 (m, 4H); 6.80 (t, 1H, J=7.3 Hz); 6.95 (d, 2H, J=8.2 Hz); 7.22 (t,2H, J=7.9 Hz); 8.69 (s, 1H); 10.35 (s, 1H). HPLC analysis on ZorbaxSB-C₁₈ column: impurities 3% (column size 4.6×150 mm; mobile phasemethanol-0.1% H₃PO₄, gradient from 50:50 to 90:10; detector UV 220 nm;sample concentration 0.55 mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₁₇H₂₅N₃O₃, %: C, 63.93; H, 7.89; N, 13.16. Found, %: C, 63.80; H, 7.89;N, 13.06.

Example 143 8-(4-Benzhydryl-piperazin-1-yl)-8-oxo-heptanoic acidhydroxyamide (PX117764)

The title compound was obtained from methyl8-(4-benzhydryl-1-piperazinyl)-4-oxooctanoate (19d) by Method Q, yield32%. M.p. 126-129° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.14-1.30 (m, 4H);1.34-1.54 (m, 4H); 1.91 (t, 2H, J=7.3 Hz); 2.15-2.32 (m, 6H); 3.38-3.50(m, 4H); 4.30 (s, 1H); 7.17-7.50 (m, 10H); 8.66 (s, 1H); 10.32 (s, 1H).HPLC analysis on Symmetry C₈ column: impurities 3.3% (column size3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),50:50; detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.3mL/min). Anal. Calcd for C₂₅H₃₃N₃O₃, %: C, 70.89; H, 7.85; N, 9.92.Found, %: C, 70.81; H, 7.63; N, 10.11.

Example 144 8-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-8-oxo-octanoic acidhydroxyamide (PX117768)

The title compound was obtained from methyl8-[4-(2-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate (19e) by Method Q,yield 34%. M.p. 135-137° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.38 (m,4H); 1.38-1.60 (m, 4H); 1.93 (t, 2H, J=7.3 Hz); 2.31 (t, 2H, J=7.2 Hz);2.82-2.98 (m, 4H); 3.50-3.62 (m, 4H); 3.78 (s, 3H); 6.84-7.02 (m, 4H);8.66 (s, 1H); 10.33 (s, 1H). HPLC analysis on Symmetry C₈ column:impurities <1.0% (column size 3.9×150 mm; mobile phase acetonitrile-0.1Mphosphate buffer (pH 2.5), 30:70; detector UV 220 nm; sampleconcentration 0.5 mg/ml; flow rate 1.1 mL/min). Anal. Calcd forC₁₉H₂₉N₃O₄, %: C, 62.79; H, 8.04; N, 11.56. Found, %: C, 62.71; H, 8.07;N, 11.64.

Method R—General Synthesis of Hydroxamic Acids from Amidoesters

To a solution of amidoester 19f-w (1 mmol) in methanol (3-5 mL), asolution of hydroxylamine hydrochloride (0.278 g, 4 mmol) in methanol (3mL) followed by a solution of NaOH (0.320 g, 8 mmol) in water (1 mL)were added. After stirring for 15-45 minutes at ambient temperature, thereaction mixture was diluted with brine and extracted with ethyl acetate(3×30 mL). The organic phase was washed with brine, evaporated underreduced pressure by adding benzene to remove traces of water severaltimes, and dried in vacuum. The crude product was crystallized orchromatographed on silica gel to give the corresponding hydroxamic acid.

Example 145 8-[4-(2-Chloro-phenyl)-piperazin-1-yl]-8-oxo octanoic acidhydroxyamide (PX118791)

The title compound was obtained from methyl ethyl8-[4-(2-chlorophenyl)-1-piperazinyl]-8-oxooctanoate (19f) using MethodR. The crude product was crystallized from acetonitrile, yield 65%. M.p.131-132° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.37 (m, 4H); 1.40-1.60 (m,4H); 1.93 (t, J=7.0 Hz, 2H); 2.33 (t, J=7.3 Hz, 2H); 2.83-3.20 (m, 4H);3.53-3.66 (m, 4H); 7.06 (dt, J=1.6 and 7.8 Hz, 1H); 7.15 (dd, J=1.4 and8.2 Hz, 1H); 7.30 (dt, J=1.4 and 8.2 Hz, 1H); 7.43 (dd, J=1.6 and 7.8Hz, 1H); 8.66 (s, 1H); 10.33 (s, 1H). HPLC analysis on Omnispher 5 C₁₈column: impurities <1% (column size 4.6×150 mm; mobile phase 45%acetonitrile+55% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm;sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd forC₁₈H₂₈ClN₃O₃*0.4H₂O, %: C, 57.64; H, 7.20; N, 11.20. Found, %: C, 57.72;H, 7.03; N, 11.24.

Example 146 8-[4-(3-Chloro-phenyl)-piperazin-1-yl]-8-oxo octanoic acidhydroxyamide (PX118792)

The title compound was obtained from ethyl8-[4-(3-chlorophenyl)-1-piperazinyl]-8-oxooctanoate (19g) using MethodR. The crude product was crystallized from acetonitrile, yield 56%. M.p.122-124° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.19-1.38 (m, 4H); 1.40-1.61 (m,4H); 1.93 (t, J=7.2 Hz, 2H); 2.29 (t, J=7.4 Hz, 2H); 2.80-3.20 (m, 4H);3.55-3.66 (m, 4H); 6.81 (d, J=7.8 Hz, 1H); 6.87-6.99 (m, 2H); 7.22 (t,J=7.8 Hz, 1H); 8.65 (d, J=1.4 Hz, 1H); 10.33 (s, 1H). HPLC analysis onZorbax SB C₁₈ column: impurities ˜2.5% (column size 4.6×150 mm; mobilephase acetonitrile-0.1M phosphate buffer (pH 2.5), gradient from 30:70to 100:0; detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate1.5 mL/min). Anal. Calcd for C₁₈H₂₆ClN₃O₃, %: C, 58.77; H, 7.12; N,11.42. Found, %: C, 58.41; H, 7.07; N, 11.44.

Example 147 7-[4-(2-Chloro-phenyl)-piperazin-1-yl]-7-oxo heptanoic acidhydroxyamide (PX118793)

The title compound was obtained from ethyl7-[4-(2-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate (19h) using MethodR. The crude product was crystallized from acetonitrile, yield 62%. M.p.128-130° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.17-1.36 (m, 2H); 1.41-1.62 (m,4H); 1.94 (t, J=7.0 Hz, 2H); 2.33 (t, J=7.3 Hz, 2H); 2.80-3.20 (m, 4H);3.54-3.67 (m, 4H); 7.06 (dt, J=1.6 and 7.8 Hz, 1H); 7.15 (dd, J=1.8 and8.0 Hz, 1H); 7.30 (dt, J=1.8 and 8.0 Hz, 1H); 7.43 (dd, J=1.6 and 7.8Hz, 1H); 8.67 (d, J=1.8 Hz, 1H); 10.33 (s, 1H). HPLC analysis onOmnispher 5 C₁₈ column: impurities ˜1.8% (column size 4.6×150 mm; mobilephase 40% acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV220 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal.Calcd for C₁₇H₂₄ClN₃O₃, %: C, 57.70; H, 6.84; N, 11.88. Found, %: C,57.76; H, 6.87; N, 11.79.

Example 148 7-[4-(3-Chloro-phenyl)-piperazin-1-yl]-7-oxo heptanoic acidhydroxyamide (PX118794)

The title compound was obtained from ethyl7-[4-(3-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate (19i) using MethodR. The crude product was crystallized from acetonitrile, yield 48%. M.p.120-122° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.17-1.34 (m, 2H); 1.40-1.59 (m,4H); 1.93 (t, J=7.3 Hz, 2H); 2.32 (t, J=7.3 Hz, 2H); 3.07-3.24 (m, 4H);3.47-3.67 (m, 4H); 6.80 (dd, J=1.5 and 8.0 Hz, 1H); 6.86-6.98 (m, 2H);7.22 (t, J=7.8 Hz, 1H); 8.65 (d, J=1.8 Hz, 1H); 10.33 (s, 1H). HPLCanalysis on Zorbax SB C₁₈ column: impurities ˜3% (column size 4.6×150mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), gradientfrom 30:70 to 100:0; detector UV 254 nm; sample concentration 0.5 mg/ml;flow rate 1.5 mL/min). Anal. Calcd for C₁₇H₂₄ClN₃O₃, %: C, 57.70; H,6.84; N, 11.88. Found, %: C, 57.74; H, 6.86; N, 11.79.

Example 149 8-[4-(Naphthalene-2-carbonyl)-piperazin-1-yl]-8-oxo octanoicacid hydroxyamide (PX118830)

The title compound was obtained from ethyl8-[4-(2-naphthoyl)-1-piperazinyl]-8-oxooctanoate (19j) using Method R.The crude product was crystallized from acetonitrile, yield 54%. M.p.133.5-134.5° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.20-1.60 (m, 8H); 1.92 (t,J=7.2 Hz, 2H); 2.20-2.40 (m, 2H); 3.28-3.76 (m, 8H); 7.50-7.66 (m, 3H);7.94-8.10 (m, 4H); 8.66 (d, J=1.6 Hz, 1H); 10.32 (s, 1H). HPLC analysison Alltima C₁₈ column: impurities 3% (column size 4.6×150 mm; mobilephase 40% acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV220 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). Anal.Calcd for C₂₃H₂₉N₃O₄, %: C, 67.13; H, 7.10; N, 10.21. Found, %: C,66.90; H, 7.09; N, 10.23.

Example 150 8-(4-Benzoyl-piperazin-1-yl)-8-oxo octanoic acidhydroxyamide (PX118831)

The title compound was obtained from ethyl8-(4-benzoyl-1-piperazinyl)-8-oxooctanoate (19k) using Method R. Thecrude product was crystallized from acetonitrile, yield 29%. M.p.100-101° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.36 (m, 4H); 1.38-1.58 (m,4H); 1.92 (t, J=7.4 Hz, 2H); 2.30 (t, J=6.6 Hz, 2H); 3.49 (m, 8H);7.38-7.50 (m, 5H); 8.66 (s, 1H); 10.32 (s, 1H). HPLC analysis on AlltimaC₁₈ column: impurities 2.5% (column size 4.6×150 mm; mobile phase 20%acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm;sample concentration 1.0 mg/ml; flow rate 1.7 mL/min). Anal. Calcd forC₁₉H₂₇N₃O₄*0.35H₂O, %: C, 62.06; H, 7.59; N, 11.43. Found, %: C, 62.03;H, 7.50; N, 11.33.

Example 151 8-[4-(4-Dimethylamino-benzoyl-piperazin-1-yl]-8-oxo octanoicacid hydroxyamide (PX118832)

The Title Compound was Obtained from Ethyl8-{4-[4-(Dimethylamino)Benzoyl]-1-piperazinyl}-8-oxooctanoate (19l)using Method R. The crude product was crystallized from acetonitrile,yield 74%. M.p. 90-92° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.30 (m, 4H);1.40-1.60 (m, 4H); 1.93 (t, J=7.2 Hz, 2H); 2.30 (t, J=7.0 Hz, 2H); 2.95(s, 6H); 3.44-3.52 (m, 8H); 6.70 (d, J=8.6 Hz, 2H); 7.29 (d, J=8.6 Hz,2H); 8.64 (s, 1H); 10.32 (s, 1H). HPLC analysis on Zorbax SB C₁₈ column:impurities ˜10% (column size 4.6×150 mm; mobile phase gradient 15 min10% acetonitrile/90% 0.1M phosphate buffer (pH 2.5)-100% 0.1M phosphatebuffer; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate1.0 mL/min). Anal. Calcd for C₂₁H₃₂N₄O₄*0.5H₂O, %: C, 61.00; H, 8.04; N,13.55. Found, %: C, 60.98; H, 7.85; N, 13.37.

Example 152 8-[4-(4-Methoxyphenyl)-piperazin-1-yl]-8-oxo octanoic acidhydroxyamide (PX118846)

The title compound was obtained from ethyl8-[4-(4-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate (19m) using MethodR. The crude product was crystallized from acetonitrile, yield 48%. M.p.149-150° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.33 (m, 4H); 1.39-1.58 (m,4H); 1.93 (t, J=7.2 Hz, 2H); 2.32 (t, J=7.4 Hz, 2H); 2.88-3.03 (m, 4H);3.52-3.61 (m, 4H); 3.68 (s, 3H); 6.83 (dt, J=9.6 and 2.8 Hz, 2H); 6.90(dt, J=9.6 and 2.8 Hz, 2H); 8.64 (s, 1H); 10.32 (s, 1H). HPLC analysison Alltima C₁₈ column: impurities 1.5% (column size 4.6×150 mm; mobilephase 25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV220 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal.Calcd for C₁₉H₂₉N₃O₄, %: C, 62.79; H, 8.04; N, 11.56. Found, %: C,62.65; H, 8.09; N, 11.53.

Example 153 8-[4-(3-Methoxyphenyl)-piperazin-1-yl]-8-oxo octanoic acidhydroxyamide (PX118847)

The title compound was obtained from ethyl8-[4-(3-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate (19n) using MethodR. The crude product was crystallized from acetonitrile, yield 69%. M.p.122-122.5° C. ¹H NMR (DMSO-d₅, HMDSO), δ: 1.18-1.36 (m, 4H); 1:39-1.58(m, 4H); 1.93 (t, J=7.0 Hz, 2H); 2.32 (t, J=7.6 Hz, 2H); 3.03-3.17 (m,4H); 3.50-3.63 (m, 4H); 3.71 (s, 3H); 6.39 (dd, J=8.0 and 2.0 Hz, 1H);6.46 (t, J=2.0 Hz, 1H); 6.52 (dd, J=8.0 and 2.0 Hz, 1H); 7.12 (t, J=8.0Hz, 1H); 8.63 (d, J=1.6 Hz, 1H); 10.31 (s, 1H). HPLC analysis on AlltimaC₁₈ column: impurities 1% (column size 4.6×150 mm; mobile phase 25%acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm;sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₁₉H₂₉N₃O₄, %: C, 62.79; H, 8.04; N, 11.56. Found, %: C, 62.65; H, 8.06;N, 11.43.

Example 154N-Hydroxy-8-[4-(4-nitrophenyl)-1-piperazinyl]-8-oxooctanamide (PX118849)

The title compound was obtained from ethyl8-[4-(4-nitrophenyl)-1-piperazinyl]-8-oxooctanoate (19o) using Method R.The crude product was crystallized from acetonitrile, yield 31%. M.p.125-127° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.20-1.28 (m, 4H); 1.33-1.50 (m,4H); 1.93 (t, J=7.6 Hz, 2H); 2.33 (t, J=7.2 Hz, 2H); 3.40-3.70 (m, 8H);7.00 (d, J=9.0 Hz, 2H); 8.07 (d, J=9.0 Hz, 2H); 8.67 (s, 1H); 10.33 (s,1H). HPLC analysis on Alltima C₁₈ column: impurities 2.5% (column size4.6×150 mm; mobile phase 40% acetonitrile+60% 0.1M phosphate buffer (pH2.5); detector UV 215 nm; sample concentration 0.5 mg/ml; flow rate 1.5mL/min). Anal. Calcd for C₁₈H₂₆N₄O₅, %: C, 57.13; H, 6.93; N, 14.80.Found, %: C, 57.06; H, 6.94; N, 14.72.

Example 155N-Hydroxy-8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanamide(PX118927)

The title compound was obtained from methyl8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate(19p) using Method R. The crude product was chromatographed on reversephase Silasorb CL18 with methanol-0.1% H₃PO₄ as eluent. The eluate wasevaporated, the residue was dissolved in ethyl acetate, the extract waswashed with water, evaporated, and dried. Yield 35%. Foam. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.13-1.32 (m, 4H); 1.34-1.55 (m, 4H); 1.91 (t,J=7.3 Hz, 2H); 2.17-2.31 (m, 2H); 3.24-3.57 (m, 8H, overlapped with asignal of water); 3.73 (s, 3H); 3.75 (s, 2H); 6.71 (dd, J=8.8 and 2.4Hz, 1H); 7.05 (d, J=2.4 Hz, 1H); 7.16 (br s, 1H); 7.22 (d, J=8.8 Hz,1H); 8.67 (s, 1H); 10.33 (s, 1H); 10.75 (s, 1H). HPLC analysis onKromasil C₁₈ column: impurities 5% (column size 4.6×150 mm; mobile phase20% acetonitrile+80% 0.2M acetate buffer (pH 5.0); detector UV 230 nm;sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₂₃H₃₂N₄O₅*0.25H₂O, containing 4% of inorganic impurities, %: C, 59.06;H, 7.00; N, 11.98. Found, %: C, 59.01; H, 7.02; N, 11.97.

Example 156N-Hydroxy-8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-8-oxooctanamide(PX118930)

The title compound was obtained from methyl8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-8-oxooctanoate (19r) usingMethod R. The crude product was precipitated from diethyl ether, yield35%. Foam. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.16-1.31 (m, 4H); 1.37-1.54 (m,4H); 1.93 (t, J=7.2 Hz, 2H); 2.27 (t, J=7.4 Hz, 2H); 2.41-2.55 (m, 4H,overlapped with a signal of DMSO); 2.79 (t, J=5.9 Hz, 2H); 3.39-3.49 (m,4H); 4.21 (t, J=5.9 Hz, 2H); 7.16 (dd, J=8.8 and 2.4 Hz, 1H); 7.29-7.50(m, 3H); 7.76-7.86 (m, 3H); 8.67 (s, 1H); 10.33 (s, 1H). HPLC analysison Alltima C₁₈ column: impurities 1% (column size 4.6×150 mm; mobilephase 25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV220 nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal.Calcd for C₂₄H₃₃N₃O₄*1.25H₂O, %: C, 64.05; H, 7.95; N, 9.34. Found, %:C, 64.17; H, 7.91; N, 9.28.

Example 157N-Hydroxy-8-{4-[2-(1-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide(PX118931)

The title compound was obtained from ethyl8-{4-[2-(1-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanoate (19s) usingMethod R. The crude product was precipitated from diethyl ether, yield34%. Foam. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.14-1.33 (m, 4H); 1.37-1.56 (m,4H); 1.92 (t, J=7.0 Hz, 2H); 2.21-2.36 (m, 2H); 3.22-3.61 (m, 8H,overlapped with a signal of H₂O); 3.92 (s, 2H); 7.34-7.57 (m, 3H);7.80-7.95 (m, 4H); 8.66 (s, 1H); 10.32 (s, 1H). HPLC analysis on AlltimaC₁₈ column: impurities 1% (column size 4.6×150 mm; mobile phase 50%acetonitrile+50% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm;sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd forC₂₄H₃₁N₃O₅, %: C, 65.29; H, 7.08; N, 9.52. Found, %: C, 65.15; H, 7.45;N, 9.40.

Example 158N-Hydroxy-8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1-piperazinyl}-8-oxooctanamideoxalate (PX118932)

The title compound was obtained from methyl8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1-piperazinyl}-8-oxooctanoate(19t) using Method R. The crude product (ca. 0.33 mmol) was dissolved inabs. ethanol (1.5 mL) and a solution of oxalic acid dihydrate (0.1 g,0.79 mmol) in abs. ethanol (1 mL) was added. The reaction mixture wasstirred for 2 hours at ambient temperature, the precipitate was filteredand washed with diethyl ether. The product was crystallized from ethanoland dried, yield 70%. M.p. 122-125° C. ¹H NMR (DMSO-d₆, HMDSO), δ:1.17-1.35 (m, 4H); 1.39-1.57 (m, 4H); 1.93 (t, J=7.6 Hz, 2H); 2.32 (t,J=7.4 Hz, 2H); 2.93-3.17 (m, 8H); 3.56-3.72 (m, 4H); 3.77 (s, 3H); 6.73(dd, J=8.8 and 2.2 Hz, 1H); 7.03 (d, J=2.2 Hz, 1H); 7.16 (d, J=2.2 Hz,1H); 7.23 (d, J=8.8 Hz, 2H); 10.35 (s, 1H); 10.75 (s, 1H). HPLC analysison Zorbax SB C₁₈ column: impurities ˜7% (column size 4.6×150 mm; mobilephase 15 min gradient: acetonitrile-0.1M phosphate buffer (pH 2.5);30/70-100/0; detector UV 220 nm; sample concentration 0.5 mg/ml; flowrate 1.5 mL/min). Anal. Calcd for C₂₃H₃₄N₄O₄*1.3 (COOH)₂, %: C, 56.15;H, 6.74; N, 10.23. Found, %: C, 56.00; H, 6.86; N, 10.12.

Example 1598-{4-[2-(1-Benzothiophen-3-yl)acetyl]-1-piperazinyl}-N-hydroxy-8-oxooctanamide(PX118967)

The title compound was obtained from ethyl8-{4-[2-(1-benzothiophen-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate(19u) using Method R. The crude product was crystallized fromacetonitrile, yield 35%. M.p. 140-141° C. ¹H NMR (DMSO-d₆, HMDSO), δ:1.15-1.34 (m, 4H); 1.37-1.56 (m, 4H); 1.92 (t, J=7.3 Hz, 2H); 2.29 (t,J=7.3 Hz, 2H); 3.36-3.60 (m, 8H); 3.98 (s, 2H); 7.34-7.44 (m, 2H); 7.51(s, 1H); 7.78-7.85 (m, 1H); 7.93-8.05 (m, 1H); 8.65 (s, 1H); 10.32 (s,1H). HPLC analysis on Omnispher 5 C₁₈ column: impurities 1% (column size4.6×150 mm; mobile phase 50% acetonitrile+50% 0.1M phosphate buffer (pH2.5); detector UV 215 nm; sample concentration 0.5 mg/ml; flow rate 1.3mL/min). Anal. Calcd for C₂₂H₂₉N₃O₄S, %: C, 61.23; H, 6.77; N, 9.74.Found, %: C, 60.76; H, 6.71; N, 9.82.

Example 1607-[4-(3,4-Dichlorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide(PX118989)

The title compound was obtained from ethyl7-[4-(4-dichlorophenyl)-1-piperazinyl]-7-oxoheptanoate (19v) usingMethod R. The crude product was crystallized from ethyl acetate-methanol(9:1), yield 43%. M.p. 125-126° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.14-1.34(m, 2H); 1.38-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.32 (t, J=7.0 Hz,2H); 3.07-3.26 (m, 4H); 3.48-3.63 (m, 4H); 6.94 (dd, J=8.8 and 2.9 Hz,1H); 7.14 (d, J=2.9 Hz, 1H); 7.40 (d, J=8.8 Hz, 1H); 8.67 (d, J=1.5 Hz,1H); 10.33 (s, 1H). HPLC analysis on Omnispher 5 C₁₈ column: impurities1% (column size 4.6×150 mm; mobile phase 40% acetonitrile+60% 0.1Mphosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C₁₇H₂₃Cl₂N₃O₃, %: C,52.59; H, 5.97; N, 10.82. Found, %: C, 52.50; H, 5.90; N, 10.75.

Example 1617-[4-(4-Fluorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide(PX118990)

The title compound was obtained from ethyl7-[4-(4-fluorophenyl)-1-piperazinyl]-7-oxoheptanoate (19v) using MethodR. The crude product was crystallized from ethyl acetate-methanol (9:1),yield 29%. M.p. 119-120° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.34 (m,2H); 1.39-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.32 (t, J=7.3 Hz, 2H);2.94-3.11 (m, 4H); 3.51-3.62 (m, 4H); 6.92-7.13 (m, 4H); 8.67 (s, 1H);10.33 (s, 1H). HPLC analysis on Alltima C₁₈ column: impurities 2%(column size 4.6×150 mm; mobile phase 35% acetonitrile+65% 0.1Mphosphate buffer (pH 2.5); detector UV 254 nm; sample concentration 1.0mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C₁₇H₂₄FN₃O₃, %: C, 60.52;H, 7.17; N, 12.45. Found, %: C, 60.42; H, 7.22; N, 12.32.

Example 1627-[4-(4-Chlorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide(PX118991)

The title compound was obtained from ethyl7-[4-(4-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate (19w) using MethodR. The crude product was crystallized from ethyl acetate-methanol (9:1),yield 21%. M.p. 119-121° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.19-1.34 (m,2H); 1.39-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.33 (t, J=7.3 Hz, 2H);3.01-3.18 (m, 4H); 3.50-3.64 (m, 4H); 6.95 (d, J=8.8 Hz, 2H); 7.24 (d,J=8.8 Hz, 2H); 8.67 (s, 1H); 10.33 (s, 1H). HPLC analysis on Omnispher 5C₁₈ column: impurities 2.2% (column size 4.6×150 mm; mobile phase 35%acetonitrile+65% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm;sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd forC₁₇H₂₄ClN₃O₃, %: C, 57.70; H, 6.84; N, 11.88. Found, %: C, 57.75; H,6.84; N, 11.80.

Method S—General Synthesis of Hydroxamic Acids from O-benzylHydroxamates

To a solution of O-benzylhydroxamate 22a-k (1 mmol) in methanol (5-10mL), 5% palladium on activated carbon catalyst (0.050 g) was added andthe black suspension was vigorously stirred under hydrogen atmosphereuntil initial compound disappeared. The reaction mixture was filteredthrough a small amount of silica gel (ca. 1-2 cm thin layer), thesorbent was washed with methanol, and the filtrate was evaporated invacuum. The crude product was crystallized or chromatographed on silicagel to give the corresponding hydroxamic acid.

Example 163 8-[4-(4-Cyanobenzoyl)-piperazin-1-yl]-8-oxo octanoic acidhydroxyamide (PX118844)

The title compound was obtained fromN-(benzyloxy)-8-[4-(4-cyanobenzoyl)-1-piperazinyl]-8-oxooctanamide (22a,using Method S, yield 74%. M.p. 150-150.5° C. ¹H NMR (DMSO-do, HMDSO),δ: 1.18-1.38 (m, 4H); 1.40-1.60 (m, 4H); 1.92 (t, J=7.0 Hz, 2H);2.22-2.40 (m, 2H); 3.20-3.70 (m, overlapped with a signal of H₂O); 7.61(d, J=8.0 Hz, 2H); 7.94 (d, J=8.0 Hz, 2H); 8.64 (s, 1H); 10.32 (s, 1H).HPLC analysis on Omnispher 5 C₁₈ column: impurities 2% (column size4.6×150 mm; mobile phase 20% acetonitrile+80% 0.1M phosphate buffer (pH2.5); detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0mL/min). Anal. Calcd for C₂₀H₂₆N₄O₄*0.5H₂O, %: C, 60.74; H, 6.88; N,14.17. Found, %: C, 60.83; H, 6.82; N, 13.88.

Example 164 7-Oxo-7-(4-pyridin-2-yl-piperazin-1-yl]-heptanoic acidhydroxyamide oxalate (PX118845)

The title compound was obtained fromN-(benzyloxy)-7-oxo-7-[4-(2-pyridinyl)-1-piperazinyl]heptanamide (22b),using Method S. The crude product (ca. 0.33 mmol) was dissolved in abs.ethanol (1.5 mL) and a solution of oxalic acid dihydrate (0.1 g, 0.79mmol) in abs. ethanol (1 mL) was added. The reaction mixture was stirredfor 2 hours at ambient temperature, the precipitate was filtered andwashed with diethyl ether. The product was crystallized from ethanol anddried, yield 65%. M.p. 118-122° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.20-1.40(m, 2H); 1.42-1.65 (m, 4H); 2.35 (t, J=7.2 Hz, 2H); 2.77 (t, J=7.2 Hz,2H); 3.37-3.63 (m, 8H); 6.65 (dd, J=7.2 and 5.0 Hz, 1H); 6.83 (d, J=8.2Hz, 1H); 7.55 (ddd, J=8.2, 7.2 and 1.8 Hz, 1H); 8.11 (dd, J=5.0 and 1.8Hz, 1H). HPLC analysis on Ultra Aqueous C₁₈ column: impurities 2.3%(column size 4.6×150 mm; mobile phase 5% acetonitrile+95% 0.1M phosphatebuffer (pH 2.5); detector UV 215 nm; sample concentration 0.5 mg/mL;flow rate 1.5 mL/min). Anal. Calcd for C₁₆H₂₄N₄O₃*0.5C₂H₂O₄*0.5H₂O, %:C, 54.53; H, 7.00; N, 14.96. Found, %: C, 54.43; H, 7.20; N, 14.84.

Example 1658-(4-{2-[4-(Dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooctanamide(PX118848)

The Title Compound was Obtained fromN-(Benzyloxy)-8-(4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinyl)-8-oxooctanamide(22c), using Method S. The crude product was precipitated from diethylether, yield 63%. M.p. 77-79° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.34(m, 4H); 1.36-1.56 (m, 4H); 1.92 (t, J=7.2 Hz, 2H); 2.27 (t, J=7.2 Hz,2H); 2.85 (s 6H); 3.25-3.50 (m, 8H, overlapped with a signal of H₂O);3.58 (s, 2H); 6.66 (d, J=8.2, 2H); 7.03 (d, J=8.2 Hz, 2H); 8.65 (s, 1H);10.32 (s, 1H). HPLC analysis on Alltima C₁₈ column: impurities 4%(column size 4.6×150 mm; mobile phase 15% acetonitrile+85% 0.1Mphosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C₂₂H₃₄N₄O₄*0.5H₂O, %: C,61.80; H, 8.25; N, 13.10. Found, %: C, 61.90; H, 8.18; N, 13.11.

Example 166N-Hydroxy-8-oxo-8-[4-(2-pyrimidinyl)-1-piperazinyl]octanamide (PX118850)

The title compound was obtained fromN-(benzyloxy)-8-oxo-8-[4-(2-pyrimidinyl)-1-piperazinyl]octanamide (22d),using Method S. The crude product was crystallized from methanol, yield37%. M.p. 132-133.5° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.36 (m, 4H);1.38-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.33 (t, J=7.3 Hz, 2H);3.46-3.58 (m, 4H); 3.62-3.80 (m, 4H); 6.65 (t, J=4.8 Hz, 1H); 8.37 (d,J=4.8 Hz, 2H); 8.65 (br s, 1H); 10.29 (br s, 1H). HPLC analysis onAlltima C₁₈ column: impurities 1% (column size 4.6×150 mm; mobile phase20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV 230 nm;sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₁₆H₂₅N₅O₃, %: C, 57.30; H, 7.51; N, 20.88. Found, %: C, 57.23; H, 7.58;N, 20.80.

Example 1678-{4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}-N-hydroxy-8-oxooctanamide(PX118928)

The title compound was obtained fromN-(benzyloxy)-8-(4-{3-[3-(dimethylamino)phenyl]propyl}-1-piperazinyl)-8-oxooctanamide(22e), using Method S. The crude product was crystallized fromacetonitrile, yield 45%. M.p. 103-105° C. ¹H NMR (DMSO-d₆, HMDSO), δ:1.11-1.33 (m, 4H); 1.35-1.54 (m, 4H); 1.92 (t, J=7.2 Hz, 2H); 2.26 (t,J=7.4 Hz, 2H); 2.24-2.66 (m, 8H, partially overlapped with a signal ofDMSO); 2.83 (s, 6H); 3.25-3.50 (m, 4H, partially overlapped with asignal of water); 6.64 (d, J=8.6 Hz, 2H); 7.00 (d, J=8.6 Hz, 2H); 8.67(s, 1H); 10.33 (s, 1H). HPLC analysis on Alltima C₁₈ column: impurities1% (column size 4.6×150 mm; mobile phase 8% acetonitrile+92% 0.1Mphosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C₂₂H₃₅N₄O₃, containing 1%of inorganic impurities, %: C, 64.66; H, 8.88; N, 13.71. Found, %: C,64.64; H, 8.94; N, 13.70.

Example 168N-Hydroxy-8-{4-[2-(2-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide(PX118929)

The title compound was obtained fromN-(benzyloxy)-8-{4-[2-(2-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide(22f), using Method S. The crude product was crystallized fromacetonitrile, yield 45%. M.p. 139-140.5° C. ¹H NMR (DMSO-d₆, HMDSO), δ:1.17-1.35 (m, 4H); 1.37-1.56 (m, 4H); 1.93 (t, J=7.2 Hz, 2H); 2.32 (t,J=7.0 Hz, 2H); 3.39-3.60 (m, 8H, overlapped with a signal of H₂O); 4.97(s, 2H); 7.17-7.51 (m, 4H); 7.37-7.89 (m, 3H); 8.67 (s, 1H); 10.34 (s,1H). TLC: single spot at R_(f) 0.3 (ethyl acetate-methanol, 4:1;detection—UV-254 nm). Anal. Calcd for C₂₄H₃₁N₃O₅, containing 1% ofinorganic impurities, %: C, 64.64; H, 7.01; N, 9.42. Found, %: C, 64.64;H, 6.96; N, 9.45.

Example 169N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptanamide(PX118968)

The title compound was obtained fromN-(benzyloxy)-7-{4-[3-(1H-indol-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptanamide(22g), using Method S. The crude product was crystallized frommethanol-ethyl acetate (1:2), yield 40%. M.p. 152.5-153.5° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.13-1.33 (m, 2H); 1.36-1.57 (m, 4H); 1.92 (t,J=7.0 Hz, 2H); 2.27 (t, J=7.0 Hz, 2H); 2.67 (t, J=7.3 Hz, 2H); 2.93 (t,J=7.3 Hz, 2H); 3.25-3.52 (m, 8H, overlapped with a signal of H₂O); 6.96(t, J=7.3 Hz, 1H); 7.05 (t, J=7.3 Hz, 1H); 7.14 (d, J=2.0 Hz, 1H); 7.33(d, J=7.3 Hz, 1H); 7.51 (d, J=7.3 Hz, 1H); 8.67 (s, 1H); 10.34 (s, 1H);10.78 (s, 1H). HPLC analysis on Alltima C₁₈ column: impurities 1%(column size 4.6×150 mm; mobile phase 20% acetonitrile+80% 0.1Mphosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.25mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₂₂H₃₀N₄O₄*0.5H₂O*0.1EtOAc, %: C, 62.59; H, 7.42; N, 12.81. Found, %: C,62.61; H, 7.35; N, 12.92.

Example 170N-Hydroxy-7-[4-(1H-indol-3-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide(PX118969)

The title compound was obtained fromN-(benzyloxy)-7-[4-(1H-indol-3-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide(22h), using Method S. The crude product was crystallized frommethanol-ethyl acetate (2:3), yield 52%. M.p. 86-88° C. ¹H NMR (DMSO-d₆,HMDSO), δ: 1.16-1.35 (m, 2H); 1.39-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H);2.32 (t, J=7.3 Hz, 2H); 3.43-3.70 (m, 8H); 7.04-7.21 (m, 2H); 7.44 (dd,J=7.3 and 1.5 Hz, 1H); 7.66-7.75 (m, 2H); 8.67 (s, 1H); 10.34 (s, 1H);11.62 (s, 1H). HPLC analysis on Omnispher 5 C₁₈ column: impurities 2%(column size 4.6×150 mm; mobile phase 20% acetonitrile+80% 0.1Mphosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C₂₀H₂₆N₄O₄*0.5H₂O*0.2CH₂Cl₂, containing 2% of inorganic impurities, %: C, 58.18; H, 6.56; N,13.30. Found, %: C, 58.12; H, 6.54; N, 13.33.

Example 171N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propyl]-1-piperazinyl}-7-oxoheptanamide(PX118970)

The title compound was obtained fromN-(benzyloxy)-7-{4-[3-(1H-indol-3-yl)propyl]-1-piperazinyl}-7-oxoheptanamide(22i), using Method S. The crude product was crystallized frommethanol-ethyl acetate (2:3), yield 23%. M.p. 165-166° C. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.11-1.32 (m, 2H); 1.35-1.57 (m, 4H); 1.79 (t,J=7.3 Hz, 2H); 1.92 (t, J=7.0 Hz, 2H); 2.18-2.41 (m, 10H); 2.68 (t,J=7.3 Hz, 2H); 3.42 (br s, 4H); 6.90-7.06 (m, 2H); 7.10 (s, 1H); 7.31(d, J=7.3 Hz, 1H); 7.49 (d, J=7.3 Hz, 1H); 8.66 (s, 1H); 10.32 (s, 1H);10.74 (s, 1H). HPLC analysis on μ Bondasphere Phenyl column: impurities2.5% (column size 4.6×150 mm; mobile phase 20% acetonitrile+80% 0.1Mphosphate buffer (pH 2.5); detector UV 210 nm; sample concentration 0.5mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C₂₂H₃₂N₄O₃, %: C, 65.97;H, 8.05; N, 13.99. Found, %: C, 65.85; H, 8.10; N, 13.97.

Example 172N-Hydroxy-7-[4-(1H-indol-3-ylmethyl)-1-piperazinyl]-7-oxoheptanamide(PX118978)

The title compound was obtained fromN-(benzyloxy)-7-[4-(1H-indol-3-ylmethyl)-1-piperazinyl]-7-oxoheptanamide(22j), using Method S. The crude product was crystallized frommethanol-ethyl acetate (2:3), yield 52%. M.p. 65-67° C. ¹H NMR (DMSO-d₆,HMDSO), δ: 1.10-1.30 (m, 2H); 1.34-1.56 (m, 4H); 1.91 (t, J=7.3 Hz, 2H);2.24 (t, J=7.0 Hz, 2H); 2.23-2.50 (m, 4H, overlapped with a signal ofDMSO); 3.25-3.48 (m, 4H, overlapped with a signal of water); 3.65 (s,2H); 6.97 (t, J=7.3 Hz, 1H); 7.07 (t, J=7.3 Hz, 1H); 7.23 (s, 1H); 7.34(d, J=7.3 Hz, 1H); 7.63 (d, J=7.3 Hz, 1H); 8.66 (s, 1H); 10.32 (s, 1H);10.96 (s, 1H). HPLC analysis on Omnispher C₁₈ column: impurities 2%(column size 4.6×150 mm; mobile phase 15% acetonitrile+85% 0.1Mphosphate buffer (pH 2.5); detector UV 210 nm; sample concentration 0.5mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C₂₀H₂₈N₄O₃*0.4H₂O*0.25EtOAc, containing 4% of inorganic material, %: C, 60.49; H, 7.86; N,13.44. Found, %: C, 60.65; H, 7.43; N, 13.39.

Example 1737-[4-(3,4-Dimethylphenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide(PX118994)

The title compound was obtained fromN-(benzyloxy)-7-[4-(3,4-dimethylphenyl)-1-piperazinyl]-7-oxoheptanamide(22k), using Method S. The crude product was crystallized fromacetonitrile, yield 73%. M.p. 119.5-120.5° C. ¹H NMR (DMSO-d₈, HMDSO),δ: 1.18-1.34 (m, 2H); 1.39-1.59 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.11(s, 3H); 2.16 (s, 3H); 2.32 (t, J=7.3 Hz, 2H); 2.93-3.09 (m, 4H);3.49-3.61 (m, 4H); 6.66 (dd, J=8.8 and 2.2 Hz, 1H); 6.76 (d, J=2.2 Hz,1H); 6.97 (d, J=8.8 Hz, 1H); 8.67 (d, J=1.5 Hz, 1H); 10.34 (s, 1H). HPLCanalysis on Alltima C₁₈ column: impurities <2% (column size 4.6×150 mm;mobile phase 25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5);detector UV 210 nm; sample concentration 1.0 mg/ml; flow rate 1.5mL/min). Anal. Calcd for C₁₉H₂₉N₃O₃, %: C, 65.68; H, 8.41; N, 12.09.Found, %: C, 65.65; H, 8.54; N, 12.09.

Example 174 8-[4-(3-Fluorophenyl)-piperazin-1-yl]-8-oxooctanoic acidhydroxyamide (PX118859)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 149-150.5° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.19-1.37(m, 4H); 1.39-1.58 (m, 4H); 1.93 (t, J=7.5 Hz, 2H); 2.32 (t, J=7.4 Hz,2H); 2.88-3.04 (m, 4H); 3.54-3.65 (m, 4H); 6.93-7.22 (m, 4H); 8.65 (brs, 1H); 10.32 (s, 1H). HPLC analysis on Alltima C₁₈: ˜1% impurities(column size 4.6×150 mm; mobile phase 35% acetonitrile+65% 0.1Mphosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5mg/ml; flow rate 1.5 mL/min). Anal. Calcd. for C₁₈H₂₆FN₃O₃, %: C, 61.52;H, 7.46; N, 11.96. Found, %: C, 61.45; H, 7.48; N, 11.88.

Example 1758-Oxo-8-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-octanoic acidhydroxyamide (PX118860)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 126-128° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.16-1.37(m, 4H); 1.38-1.59 (m, 4H); 1.93 (t, J=7.4 Hz, 2H); 2.33 (t, J=7.0 Hz,2H); 3.14-3.39 (m, 4H, overlapped with a signal of water); 3.52-3.65 (m,4H); 7.09 (d, J=7.6 Hz, 1H); 7.18 (s, 1H); 7.22 (d, J=8.4 Hz, 1H); 7.43(t, J=8.0 Hz, 1H); 8.64 (s, 1H); 10.32 (s, 1H). HPLC analysis onOmnispher 5 C₁₈: <1% impurities (column size 4.6×150 mm; mobile phase40% acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm;sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd forC₁₉H₂₆F₃N₃O₃, %: C, 56.85; H, 6.53; N, 10.47. Found, %: C, 56.62; H,6.48; N, 10.40.

Example 176 8-{4-[Bis-(4-fluorophenyl)-methyl]-piperazin-1-yl}-8-oxooctanoic acid hydroxyamide (PX118898)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.16-1.35 (m,4H); 1.38-1.58 (m, 4H); 1.91 (t, J=7.4 Hz, 2H); 2.15-2.30 (m, 6H);3.52-3.65 (m, 4H, overlapped with a signal of water); 4.39 (s, 1H); 7.13(t, J=8.6 Hz, 4H); 7.44 (dd, J=8.6 and 5.6 Hz, 4H); 8.65 (br s, 1H);10.31 (br s, 1H). HPLC analysis on Alltima C₁₈: ˜3.5% impurities.(column size 4.6×150 mm; mobile phase 70% acetonitrile+30% 0.1Mphosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C₂₅H₃₁F₂N₃O₃*0.25H₂O, %:C, 64.71; H, 6.84; N, 9.06. Found, %: C, 64.50; H, 6.81; N, 8.90.

Example 177 8-(3-Methyl-4-m-tolyl-piperazin-1-yl)-8-oxo octanoic acidhydroxyamide (PX118899)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 75-76° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 0.82 and 0.90(d and d, J=6.6 Hz, 3H); 1.14-1.35 (m, 4H); 1.39-1.59 (m, 4H); 1.93 (t,J=7.2 Hz, 2H); 2.24 (s, 3H); 2.13-2.42 (m, 2H); 2.80-3.53 (m, 5H, partlyoverlapped with a signal of H₂O); 3.62-4.31 (m, 2H); 6.59 (d, J=7.8 Hz,1H); 6.69 (d, J=7.8 Hz, 1H); 6.72 (s, 1H); 7.09 (t, J=7.8 Hz, 1H); 8.65(s, 1H); 10.32 (s, 1H). HPLC analysis on Omnispher 5 C₁₈: ˜1.8%impurities (column size 4.6×150 mm; mobile phase 30% acetonitrile+70%0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration1.0 mg/ml; flow rate 1.2 mL/min). Anal. Calcd. for C₂₀H₃₁N₃O₃, %: C,66.45; H, 8.64; N, 11.62. Found, %: C, 66.43; H, 8.67; N, 11.52.

Example 178 8-[4-(2-1H-Indol-3-yl-acetyl)-piperazin-1-yl]-8-oxo octanoicacid hydroxyamide (PX118900)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.10-1.31 (m,4H); 1.34-1.56 (m, 4H); 1.93 (t, J=7.2 Hz, 2H); 2.18-2.35 (m, 2H);3.20-3.58 (m, 8H, overlapped with a signal of H₂O); 3.79 (s, 2H); 6.96(t, J=7.0 Hz, 1H); 7.07 (t, J=7.0 Hz, 1H); 7.21 (s, 1H); 7.34 (d, J=7.8Hz, 1H); 7.55 (d, J=7.8 Hz, 1H); 8.65 (s, 1H); 10.32 (s, 1H); 10.93 (s,1H). HPLC analysis on Alltima C₁₈: ˜7.5% impurities (column size 4.6×150mm; mobile phase 30% acetonitrile+70% 0.1M phosphate buffer (pH 2.5);detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.0mL/min). Anal. Calcd. for C₂₂H₃₀N₄O₄*0.1H₂O*0.1EtOAc., containing 3% ofinorganic impurities, %: C, 61.39; H, 7.13; N, 12.78. Found, %: C,61.45; H, 7.08; N, 12.81.

Example 179 8-(4-Diphenylacetyl-piperazin-1-yl)-8-oxo octanoic acidhydroxyamide (PX118901)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.14-1.30 (m,4H); 1.34-1.54 (m, 4H); 1.93 (t, J=7.2 Hz, 2H); 2.17-2.32 (m, 2H);3.09-3.21 (m, 2H); 3.30-3.58 (m, 6H, overlapped with a signal of H₂O);5.55 (s, 1H); 7.15-7.37 (m, 10H); 8.66 (s, 1H); 0.33 (s, 1H). HPLCanalysis on Omnispher 5 C₁₈: ˜2.2% impurities. (column size 4.6×150 mm;mobile phase 60% acetonitrile+40% 0.1M phosphate buffer (pH 2.5);detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.2mL/min.) Anal Calcd for C₂₆H₃₃N₃O₄*0.5 MeOH, %: C, 68.07; H, 7.54; N,8.99. Found, %: C, 68.04; H, 7.23; N, 8.99.

Example 180 8-[4-(2-Naphthalen-2-yl-acetyl)-piperazin-1-yl]-8-oxooctanoic acid hydroxyamide (PX118902)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.12-1.32 (m,4H); 1.35-1.56 (m, 4H); 1.92 (t, J=7.4 Hz, 2H); 2.28 (t, J=6.8 Hz, 2H);3.26-3.58 (m, 8H, overlapped with a signal of H₂O); 3.91 (s, 2H); 7.39(dd, J=8.4 and 1.8 Hz, 1H); 7.45-7.54 (m, 2H); 7.73 (s, 1H); 7.79-7.92(m, 3H); 8.67 (s, 1H); 10.33 (s, 1H). HPLC analysis on Alltima C₁₈: ˜5%impurities (column size 4.6×150 mm; mobile phase 40% acetonitrile+60%0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration0.5 mg/ml; flow rate 1.3 mL/min.) Anal. Calcd. for C₂₄H₃₁N₃O₄*0.75H₂O,%: C, 65.66; H, 7.46; N, 9.57. Found, %: C, 65.52; H, 7.40; N, 9.43.

Example 181 8-{4-[4-(1-Hydroxyimino-ethyl)-phenyl]-piperazin-1-yl}-8-oxooctanoic acid hydroxyamide (PX118903)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 147-147.5° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.18-1.35(m, 4H); 1.37-1.57 (m, 4H); 1.93 (t, J=7.4 Hz, 2H); 2.09 (s, 3H); 2.33(t, J=7.2 Hz, 2H); 3.06-3.25 (m, 4H); 3.51-3.65 (m, 4H); 6.94 (d, J=8.8Hz, 2H); 7.51 (d, J=8.8 Hz, 2H); 8.65 (s, 1H); 10.32 (s, 1H); 10.86 (s,1H). HPLC analysis on Zorbax SB 5 C₁₈: ˜5% of acetophenone derivative(sample contains ca. 5% of the corresponding methylketone8-[4-(4-acetylphenyl)-1-piperazinyl]-N-hydroxy-8-oxooctanamide). (columnsize 4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH2.5), gradient 15 min from 20:80 to 100:0; detector UV 254 nm; sampleconcentration 0.5 mg/ml; flow rate 1.0 mL/min.) Anal. Calcd. forC₂₀H₃₀N₄O₄ containing 5% of the acetophenone C₂₀H₂₉N₃O₄, %: C, 61.63; H,7.75; N, 14.20. Found, %: C, 61.67; H, 7.76; N, 13.76.

Example 182 8-Oxo-8[4-(3-phenylallyl)-piperazin-1-yl]-octanoic acidhydroxyamide (PX118904)

The title compound was obtained using methods analogous to thosedescribed above. M.p. foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.14-1.32 (m,4H); 1.36-1.55 (m, 4H); 1.93 (t, J=7.3 Hz, 2H); 2.19-2.45 (m, 6H); 3.10(d, J=6.6 Hz, 2H); 3.27-3.51 (m, 4H, overlapped with a signal of H₂O);6.29 (dt, J=6.60 and 16.2 Hz, 1H); 6.54 (d, J=16.2 Hz, 1H); 7.15-7.48(m, 3H); 7.44 (d, J=6.6 Hz, 2H); 8.67 (br s, H); 10.33 (s, 1H). HPLCanalysis on Alltima C₁₈: ˜5% impurities (column size 4.6×150 mm; mobilephase 20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV220 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min.) Anal.Calcd. for C₂₁H₃₁N₃O₃*0.5H₂O, %: C, 65.94; H, 8.43; N, 10.99. Found, %:C, 66.05; H, 8.28; N, 10.94.

Example 183 8-[4-(2-Naphthalen-2-yl-ethyl)-piperazin-1-yl]-8-oxooctanoic acid hydroxyamide (PX118908)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 118-120° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.16-1.34(m, 4H); 1.36-1.56 (m, 4H); 1.92 (t, J=7.3 Hz, 2H); 2.27 (t, J=7.6 Hz,2H); 2.34-2.55 (m, 4H, overlapped with a signal of DMSO); 2.63 (t, J=8.4Hz, 2H); 2.92 (t, J=8.4 Hz, 2H); 3.28-3.52 (m, 4H, overlapped with asignal of H₂O); 7.37-7.53 (m, 3H); 7.73 (s, 1H); 7.77-7.91 (m, 3H); 8.67(s, 1H); 10.33 (s, 1H). HPLC analysis on Omnispher 5 C₁₈: ˜1.5%impurities (column size 4.6×150 mm; mobile phase 25% acetonitrile+75%0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration0.5 mg/ml; flow rate 1.2 mL/min.) Anal. Calcd. for C₂₄H₃₃N₃O₃, %: C,70.04; H, 8.08; N, 10.21. Found, %: C, 69.31; H, 8.11; N, 10.20.

Example 184 8-[4-(2,2-Diphenyl-ethyl)-piperazin-1-yl]-8-oxo octanoicacid hydroxyamide (PX118909)

The title compound was obtained using methods analogous to thosedescribed above. M.p. 117-118° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.12-1.31(m, 4H); 1.34-1.54 (m, 4H); 1.91 (t, J=7.4 Hz, 2H); 2.23 (t, J=7.4 Hz,2H); 2.31-2.48 (m, 4H, overlapped with a signal of DMSO); 2.94 (d, J=7.6Hz, 2H); 3.26-3.48 (m, 4H, overlapped with a signal of H₂O); 4.26 (t,J=7.6 Hz, 1H); 7.09-7.40 (m, 10H); 8.65 (s, 1H); 10.31 (s, 1H). HPLCanalysis on Alltima C₁₈: <1% impurities. (column size: 4.6×150 mm;mobile phase 25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5);detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.15mL/min.) Anal. Calcd. for C₂₆H₃₅N₃O₃, %: C, 71.37; H, 8.06; N, 9.60.Found, %: C, 71.01; H, 8.11; N, 9.59.

Biological Activity

Candidate compounds were assessed for their ability to inhibitdeacetylase activity (biochemical assays) and to inhibit cellproliferation (cell-based antiproliferation assays), as described below.

Primary Assay (1): Deacetylase Activity

Briefly, this assay relies on the release of radioactive acetate from aradioactively labelled histone fragment by the action of HDAC enzyme.Test compounds, which inhibit HDAC, reduce the yield of radioactiveacetate. Signal (e.g., scintillation counts) measured in the presenceand absence of a test compound provide an indication of that compound'sability to inhibit HDAC activity. Decreased activity indicates increasedinhibition by the test compound.

The histone fragment was an N-terminal sequence from histone H4, and itwas labelled with radioactively labelled acetyl groups using tritiatedacetylcoenzyme A (coA) in conjunction with an enzyme which is thehistone acetyltransferase domain of the transcriptional coactivatorp300. 0.33 mg of peptide H4 (the N-terminal 20 amino acids of histoneH4, synthesized using conventional methods) were incubated withHis6-tagged p300 histone acetyltransferase domain (amino acids1195-1673, expressed in E. coli strain BLR(DE3)pLysS (Novagen, Cat. No.69451-3) and 3H-acetyl coA (10 μL of 3.95 Ci/mmol; from Amersham) in atotal volume of 300 μL of HAT buffer (50 mM TrisCl pH 8, 5% glycerol, 50mM KCl, 0.1 mM ethylenediaminetetraacetic acid (EDTA), 1 mMdithiothreitol (DTT) and 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride(AEBSF)). The mixture was incubated at 30° C. for 45 min after which theHis-p300 was removed using nickel-trinitriloacetic acid agarose (Qiagen,Cat No. 30210). The acetylated peptide was then separated from freeacetyl coA by size exclusion chromatography on Sephadex G-15 (SigmaG-15-120), using distilled H₂O as the mobile phase.

After purification of the radiolabelled histone fragment, it wasincubated with a source of HDAC (e.g., an extract of HeLa cells (a richsource of HDAC), recombinantly produced HDAC1 or HDAC2) and any releasedacetate was extracted into an organic phase and quantitativelydetermined using scintillation counting. By including a test compoundwith the source of HDAC, that compound's ability to inhibit the HDAC wasdetermined.

Primary Assay (2): Deacetylase Activity: Fluorescent Assay

Alternatively, the activity of the compounds as HDAC inhibitors wasdetermined using a commercially available fluorescent assay kit: (Fluorde Lys™, BioMol Research Labs, Inc., Plymouth Meeting, USA). HeLaextract was incubated for 1 hour at 37° C. in assay buffer (25 mM HEPES,137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, pH 8.0) with 15 μM acetylatedsubstrate in the presence of test compound (HDAC inhibitor). The extentof deacetylation was determined by the addition of 50 μL of a 1-in-500dilution of Developer, and measurement of the fluorescence (excitation355 nm, emission 460 nm), according to the instructions provided withthe kit.

Extensive comparative studies have shown that Primary Assay (1) andPrimary Assay (2), discussed above, yield equivalent results. PrimaryAssay results reported herein are (a) exclusively from (1); (b)exclusively from (2); or (c) from both (1) and (2).

HeLa Cell Extract

The HeLa cell extract was made from HeLa cells (ATCC Ref. No. CCL-2) byfreeze-thawing three times in 60 mM TrisCl pH 8.0, 450 mM NaCl, 30%glycerol. Two cell volumes of extraction buffer were used, andparticulate material was centrifuged out (20800 g, 4° C., 10 min). Thesupernatant extract having deacetylase activity was aliquoted and frozenfor storage.

Recombinantly Produced HDAC1 and HDAC2

Recombinant plasmids were prepared as follows.

Full length human HDAC1 was cloned by PCR using a λgt11 Jurkat cDNAlibrary (Clontech-HL5012b). The amplified fragment was inserted into theEcoRI-SalI sites of pFlag-CTC vector (Sigma-E5394), in frame with theFlag tag. A second PCR was carried out in order to amplify a fragmentcontaining the HDAC1 sequence fused to the Flag tag. The resultingfragment was subcloned into the EcoRI-Sac1 sites of the baculovirustransfer vector pAcHTL-C (Pharmingen-21466P).

Full length mouse HDAC2 was subcloned into pAcHLT-A baculovirus transfervector (Pharmingen-21464P) by PCR amplification of the EcoRI-Sac1fragment from a HDAC2-pFlag-CTC construct.

Recombinant protein expression and purification was performed asfollows.

HDAC1 and HDAC2 recombinant baculoviruses were constructed usingBaculoGold Transfection Kit (Pharmingen-554740). Transfer vectors wereco-transfected into SF9 insect cells (Pharmingen-21300C). Amplificationof recombinant viruses was performed according to the PharmingenInstruction Manual. SF9 cells were maintained in serum-free SF900 medium(Gibco 10902-096).

For protein production, 2×10⁷ cells were infected with the appropriaterecombinant virus for 3 days. Cells were then harvested and spun at3,000 rpm for 5 minutes. They were then washed twice in PBS andresuspended in 2 pellet volumes of lysis buffer (25 mM HEPES pH 7.9, 0.1mM EDTA, 400 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Resuspendedcells were frozen on dry ice and thawed at 37° C. 3 times andcentrifuged for 10 minutes at 14,000 rpm. The supernatant was collectedand incubated with 300 μl of 50% Ni-NTA agarose bead slurry(Qiagen-30210). Incubation was carried out at 4° C. for 1 hour on arotating wheel. The slurry was then centrifuged at 500 g for 5 minutes.Beads were washed twice in 1 ml of wash buffer (25 mM HEPES pH7.9, 0.1mM EDTA, 150 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Protein waseluted 3 times in 300 μl elution buffer (25 mM HEPES pH 7.9, 0.1 mMEDTA, 250 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF) containingincreasing concentrations of imidazole: 0.2 M, 0.5 M and 1 M. Eachelution was performed for 5 minutes at room temperature. Eluted proteinwas kept in 50% glycerol at −70° C.

Assay Method

A source of HDAC (e.g., 2 μL of crude HeLa extract, 5 μL of HDAC1 orHDAC2; in elution buffer, as above) was incubated with 3 μL ofradioactively labelled peptide along with appropriate dilutions ofcandidate compounds (1.5 μL) in a total volume of 150 μL of buffer (20mM Tris pH 7.4, 10% glycerol). The reaction was carried out at 37° C.for one hour, after which the reaction was stopped by adding 20 μL of 1M HCl/0.4 M sodium acetate. Then, 750 μL of ethyl acetate was added, thesamples vortexed and, after centrifugation (14000 rpm, 5 min), 600 μLfrom the upper phase were transferred to a vial containing 3 mL ofscintillation liquid (UltimaGold, Packard, Cat. No. 6013329).Radioactivity was measured using a Tri-Carb 2100TR Liquid ScintillationAnalyzer (Packard).

Percent activity (% activity) for each test compound was calculated as:% activity={(S ^(C) −B)/(S ^(o) −B)}×100wherein S^(C) denotes signal measured in the presence of enzyme and thecompound being tested, S^(o) denotes signal measured in the presence ofenzyme but in the absence of the compound being tested, and B denotesthe background signal measured in the absence of both enzyme andcompound being tested. The IC50 corresponds to the concentration whichachieves 50% activity.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 1, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Secondary Assay: Cell Proliferation

Compounds with HDAC inhibition activity, as determined using the primaryassay, were subsequently evaluated using secondary cell-based assays.The following cell lines were used:

HeLa—Human cervical adenocarcinoma cell line (ATCC ref. No. CCL-2).

K11—HPV E7 transformed human keratinocyte line provided by PidderJansen-Duerr, Institut für Biomedizinische Altemsforschung, Innsbruck,Austria.

NHEK-Ad—Primary human adult keratinocyte line (Cambrex Corp., EastRutherford, N.J., USA).

JURKAT—Human T-cell line (ATCC no. TIB-152).

Assay Method

Cells were cultured, exposed to candidate compounds, and incubated for atime, and the number of viable cells was then assessed using the CellProliferation Reagent WST-1 from Boehringer Mannheim (Cat. No. 1 644807), described below.

Cells were plated in 96-well plates at 3-10×10³ cells/well in 100 μL ofculture medium. The following day, different concentrations of candidatecompounds were added and the cells incubated at 37° C. for 48 h.Subsequently, 10 μL/well of WST-1 reagent was added and the cellsreincubated for 1 hour. After the incubation time, absorbance wasmeasured.

WST-1 is a tetrazolium salt which is cleaved to formazan dye by cellularenzymes. An expansion in the number of viable cells results in anincrease in the overall activity of mitochondrial dehydrogenases in thesample. This augmentation in the enzyme activity leads to an increase inthe amount of formazan dye formed, which directly correlates to thenumber of metabolically active cells in the culture. The formazan dyeproduced is quantified by a scanning multiwell spectrophotometer bymeasuring the absorbance of the dye solution at 450 nm wavelength(reference wavelength 690 nm).

Percent activity (% activity) in reducing the number of viable cells wascalculated for each test compound as:% activity={(S ^(C) −B)/(S ^(o) −B)}×100wherein S^(C) denotes signal measured in the presence of the compoundbeing tested, S^(o) denotes signal measured in the absence of thecompound being tested, and B denotes the background signal measured inblank wells containing medium only. The IC50 corresponds to theconcentration which achieves 50% activity. IC50 values were calculatedusing the software package Prism 3.0 (GraphPad Software Inc., San Diego,Calif.), setting top value at 100 and bottom value at 0.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 2, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Screening in Mice with Intraperitoneal P388 Tumour

Female B6D2F1 hybrid mice weighing 19-23 grams were inoculated with thetumour cell line P388 (10⁶ cells in 0.2 mL) intraperitoneally (IP).Inoculation of tumour cells was performed on a Friday and treatment withcompounds at a dose of 64 μmol/kg/day started on Day 3 (Monday). Thecompounds were given as a single daily IP dose for five consecutivedays. Compounds were dissolved in DMSO, at a concentration correspondingto 50 μL injection volume per treatment. Treatments were given at thesame hour of the day (within one hour). Five mice in each group weretreated with compounds, and with each series of experiments, controlgroups (not treated, and DMSO-treated) were included. Moribund mice wereeuthanised, and the day of death was recorded. Log-rank analysis of thesurvival data was performed using the statistical software SAS v8.1 (SASInstitute, Cary, N.C., USA).

Biological Data

IC50 (or percent activity) data for several compounds of the presentinvention, as determined using the assays described above are summarisedin Table 1 and Table 2, below.

The results of in vivo studies of mice with intraperitoneal P388 tumourfor several compounds of the present invention, using the methodsdescribed above, are summarised in Table 3.

TABLE 1 Biochemical Assay Data HDAC Inhibition Compound (IC50 unlessotherwise specified) No. Ref. HeLa HDAC1 HDAC2 1 TSA  5 nM 15 nM 17 nM 2SAHA 189 nM — — 3 PX117403 28% @ 500 nM — — 4 PX117404 35% @ 500 nM — —5 PX117764 785 nM — — 6 PX117768 175 nM — — 7 PX118490 59% @ 100 nM — —8 PX118491 47% @ 100 nM — — 9 PX118807 60% @ 100 nM — — 10 PX118810  46nM — — 11 PX118811  42 nM — — 12 PX118812  26 nM — — 13 PX118791  36 nM— — 14 PX118792  34 nM — — 15 PX118793 188 nM — — 16 PX118794  74 nM — —17 PX118830 133 nM — — 18 PX118831 194 nM — — 19 PX118832 212 nM — — 20PX118844 286 nM — — 21 PX118846  3.4 nM — — 22 PX118847  31 nM — — 23PX118848 44% @ 100 nM — — 24 PX118849  26 nM — — 25 PX118850  70 nM — —

TABLE 2 Cell-Based Antiproliferation Assay Data Cell ProliferationInhibition WST-1 Compound IC50 unless otherwise specified) No. Ref. HeLaK11 NHEK-AD Jurkat TSA  350 nM 0.38 μM  0.2 μM   42 nM Oxamflatin — 4.82μM 3.53 μM  170 nM MS-275 — 9.16 μM  3.1 μM  365 nM SAHA — 6.82 μM 5.37μM  750 nM 1 PX117403 — — — — 2 PX117404 — — — — 3 PX117764 29.2 μM 9.45μM — 2.68 μM 4 PX117768 3.30 μM 8.67 μM — 1.04 μM 5 PX118490 1.00 μM2.49 μM —  460 nM 6 PX118491   18 μM 8.24 μM — 3.21 μM

TABLE 3 In Vivo Studies of Mice with Intraperitoneal P388 TumourCompound Log rank statistic Wilcoxon statistic No. of mice — 6.81731556.0 25 DMSO 6.4056 1290.0 20 PX118490 −3.3797 −654.0 5 PX118807−4.6177 −750.0 5 PX118871 −3.4210 −605.0 5 PX118875 −3.0949 −525.0 5PX118882 −4.9869 −613.0 5 PX118893 −3.5651 −725.0 5 PX118905 −4.0610−565.0 5 PX118907 −4.1247 −817.0 5 PX118910 −9.6221 −869.0 5

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention as setout in the appended claims.

REFERENCES

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided herein. Each of these references is incorporated herein byreference in its entirety into the present disclosure.

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1. A method for the treatment of a condition selected from melanoma orleukemia or cervical cancer comprising administering atherapeutically-effective amount of a compound of the following formulaor a pharmaceutically acceptable salt thereof:

wherein: the piperazin-1,4-diyl group is optionally substituted at oneor more the 2-, 3-, 5-, and 6-positions with C₁₋₄alkyl; Q¹ is a covalentbond; saturated C₁₋₃alkylene optionally substituted with -Ph; partiallyunsaturated C₂₋₃alkylene; or —O—C₁₋₃alkylene; either: J¹ is a covalentbond or —C(═O)— and J² is —C(═O)—; or: J¹ is a covalent bond and J² is—S(═O)₂—; Q² is —(CH₂)₅—, —(CH₂)₈₋₃—(CH₂)₇₋₃—(CH₂)₈—, orphenylene-ethenylene; Cy is phenyl, pyridinyl, furanyl, indolyl,pyrrolyl, imidazolyl, pyrazinyl, pyridizinyl, naphthyl, quinolinyl,indolyl, benzimidazolyl, benzothiofuranyl, fluorenyl, acridinyl, orcarbazolyl; and is optionally substituted.
 2. A method according toclaim 1, wherein: J¹ is a covalent bond or —C(═O)—; J² is —C(═O)—; andQ² is —(CH₂)₅—, —(CH₂)₈—, —(CH₂)₇—, or —(CH₂)₈—.
 3. A method accordingto claim 1, wherein: J¹ is a covalent bond; J² is —S(═O)₂—; and Q² isphenylene-ethenylene.
 4. A method according to claim 2, wherein Q¹ is acovalent bond.
 5. A method according to claim 3, wherein Q¹ is acovalent bond.
 6. A method according to claim 2, wherein Q¹ is —CH₂—,—CH(Ph)-, —CH₂CH₂—, —CH(Ph)CH₂—, —CH₂CH₂CH₂—, —CH═CHCH₂—, —O—CH₂—, or—O—CH₂CH₂—.
 7. A method according to claim 3, wherein Q¹ is —CH₂—,—CH(Ph)-, —CH₂CH₂—, —CH(Ph)CH₂—, —CH₂CH₂CH₂—, —CH═CHCH₂—, —O—CH₂—, or—O—CH₂CH₂—.
 8. A method according to claim 2, wherein Cy is phenyl, andis optionally substituted with one or more groups selected from: —F,—Cl, —Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH,—OMe, —OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and—CN.
 9. A method according to claim 3, wherein Cy is phenyl, and isoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH, —OMe,—OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and —CN.10. A method according to claim 4, wherein Cy is phenyl, and isoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH, —OMe,—OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and —CN.11. A method according to claim 5, wherein Cy is phenyl, and isoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH, —OMe,—OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and —CN.12. A method according to claim 6, wherein Cy is phenyl, and isoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH, —OMe,—OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and —CN.13. A method according to claim 7, wherein Cy is phenyl, and isoptionally substituted with one or more groups selected from: —F, —Cl,—Br, —I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, —CF₃, —OH, —OMe,—OEt, —O(iPr), —O(tBu), —OCF₃, —NMe₂, —NEt₂, morpholino, —NO₂, and —CN.14. A method according to claim 1, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts thereof:


15. A method according to claim 1, wherein the compound is selected fromthe following compounds and pharmaceutically acceptable salts thereof:


16. A method according to claim 1, comprising administering atherapeutically-effective amount of the following compound or apharmaceutically acceptable salt thereof:


17. A method according to claim 1, wherein the condition is melanoma.18. A method according to claim 2, wherein the condition is melanoma.19. A method according to claim 3, wherein the condition is melanoma.20. A method according to claim 4, wherein the condition is melanoma.21. A method according to claim 5, wherein the condition is melanoma.22. A method according to claim 6, wherein the condition is melanoma.23. A method according to claim 7, wherein the condition is melanoma.24. A method according to claim 8, wherein the condition is melanoma.25. A method according to claim 9, wherein the condition is melanoma.26. A method according to claim 10, wherein the condition is melanoma.27. A method according to claim 11, wherein the condition is melanoma.28. A method according to claim 12, wherein the condition is melanoma.29. A method according to claim 13, wherein the condition is melanoma.30. A method according to claim 14, wherein the condition is melanoma.31. A method according to claim 15, wherein the condition is melanoma.32. A method according to claim 16, wherein the condition is melanoma.33. A method according to claim 1, wherein the condition is leukemia.34. A method according to claim 2, wherein the condition is leukemia.35. A method according to claim 3, wherein the condition is leukemia.36. A method according to claim 4, wherein the condition is leukemia.37. A method according to claim 5, wherein the condition is leukemia.38. A method according to claim 6, wherein the condition is leukemia.39. A method according to claim 7, wherein the condition is leukemia.40. A method according to claim 8, wherein the condition is leukemia.41. A method according to claim 9, wherein the condition is leukemia.42. A method according to claim 10, wherein the condition is leukemia.43. A method according to claim 11, wherein the condition is leukemia.44. A method according to claim 12, wherein the condition is leukemia.45. A method according to claim 13, wherein the condition is leukemia.46. A method according to claim 14, wherein the condition is leukemia.47. A method according to claim 15, wherein the condition is leukemia.48. A method according to claim 16, wherein the condition is leukemia.49. A method according to claim 1, wherein the condition is cervicalcancer.
 50. A method according to claim 2, wherein the condition iscervical cancer.
 51. A method according to claim 3, wherein thecondition is cervical cancer.
 52. A method according to claim 4, whereinthe condition is cervical cancer.
 53. A method according to claim 5,wherein the condition is cervical cancer.
 54. A method according toclaim 6, wherein the condition is cervical cancer.
 55. A methodaccording to claim 7, wherein the condition is cervical cancer.
 56. Amethod according to claim 8, wherein the condition is cervical cancer.57. A method according to claim 9, wherein the condition is cervicalcancer.
 58. A method according to claim 10, wherein the condition iscervical cancer.
 59. A method according to claim 11, wherein thecondition is cervical cancer.
 60. A method according to claim 12,wherein the condition is cervical cancer.
 61. A method according toclaim 13, wherein the condition is cervical cancer.
 62. A methodaccording to claim 14, wherein the condition is cervical cancer.
 63. Amethod according to claim 15, wherein the condition is cervical cancer.64. A method according to claim 16, wherein the condition is cervicalcancer.